- Open Access
Genetic and molecular biology of gastric cancer among Iranian patients: an update
Egyptian Journal of Medical Human Genetics volume 23, Article number: 17 (2022)
There is a declining trend of gastric cancer (GC) incidence in the world during recent years that is related to the development of novel diagnostic methods. However, there is still a high ratio of GC mortality among the Iranian population that can be associated with late diagnosis. Despite various reports about the novel diagnostic markers, there is not any general and standard diagnostic panel marker for Iranian GC patients. Therefore, it is required to determine an efficient and general panel of molecular markers for early detection.
Main body of the abstract
In the present review, we summarized all of the reported markers until now among Iranian GC patients to pave the way for the determination of a population-based diagnostic panel of markers. In this regard, we categorized these markers in different groups based on their involved processes to know which molecular process is more frequent during the GC progression among Iranians.
We observed that the non-coding RNAs are the main factors involved in GC tumorigenesis in this population.
Gastric cancer (GC) is one of the leading causes of cancer-related deaths in Iran with a mortality rate of 8,000 cases per year . GC incidence has a noticeable declining trend during the recent decades in the world; however, it has still a high incidence among the Iranian population. Despite novel therapeutic modalities, it has still a poor prognosis and low survival rate . GC is more frequent in males compared with females . East Asia, East Europe, and South America are the hotspots of GC incidences in the world . Ethnic is also the other important determining factor involved in incidence variation in different populations . Different genetic and environmental factors are involved in tumor progression . It has been shown that Helicobacter pylori (H.pylori) infection and smoking are the main environmental risk factors of GC in Iran. Although management of such environmental risk factors is the main way to reduce the GC incidence, early detection can improve the overall survival rates . GC is mainly diagnosed in advanced tumor stages with a high chemoresistance [8, 9]. GC has a poor prognosis in advanced stage patients; however, gastrectomy can be effective following the early diagnosis that improves the patients survival [10, 11]. The majority of GC patients have not any access to the endoscopy as a screening method because of the high cost . Therefore, the introduction of molecular mechanisms involved in early tumor stages will be helpful to design novel diagnostic methods for the early detection of GC. In the present review, we have summarized all of the significant reported molecular factors among Iranian GC patients (Table 1). We categorized all of the reported factors based on their involved molecular processes (Fig. 1) to know more about the molecular biology of GC among Iranian patients.
Cell cycle, DNA repair, and apoptosis
Cell cycle deregulation triggers the aberrant cell proliferation that results in genetic instability in tumor cells. DNA-repair and cell-cycle checkpoints are the pivotal cellular processes that enable the cells to deal with DNA damages. Neoplastic transformation is due to the genetic changes which are facilitated in tumor cells through deregulation of DNA repair and replication. Both checkpoint controls and DNA repair systems have pivotal roles in genome stability. Cell cycle progression is regulated by multiple checkpoints which evaluate the growth signals, DNA integrity, and cell size. Cyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CKIs) are the positive and negative regulators of cell cycle progression, respectively. Therefore, CDKs activation or CKIs suppression triggers tumorigenesis . P16 is a tumor suppressor that induces cell cycle arrest through the inhibition of CDK4 and CDK6. Moreover, it suppresses the pRb phosphorylation and subsequent transcription factors which are involved in G1 checkpoint transition . The methylation status of p16 promoter sequence was evaluated in a group of Iranian GC patients. Promoter hyper methylation was observed in 44.2% of tissues and 26.9% of sera in patients. Regarding the lower ratio of methylation in well-differentiated tumors, p16 hyper methylation is probably correlated with malignant tumors. P16 was introduced as an efficient serum marker for the early detection of GC among Iranian patients .
Microsatellite instability is directly related to the mismatch repair system . The role of hMLH1 promoter methylation as one of the components of MMR system was assessed among a subpopulation of Iranian GC cases. There was a significant correlation between methylation status of hMLH1 and tumor stages, in which the majority of hyper-methylated tumors were in advanced stages. Therefore, hMLH1 hyper methylation results in lower GC progression among Iranian patients compared with other countries . Beyond the different checkpoint controls, cell cycle regulators, and DNA repair, there is also another barrier for the tumorigenesis in which the cells will be forced to undergo programmed cell death (apoptosis). P53 as a tumor suppressor gene is associated with cell-cycle arrest and apoptosis. It has been reported that there was a high frequency of p53 protein upregulation in cardia compared with the antrum adenocarcinoma in a subpopulation of Iranian GC cases .
SRBC is also a tumor suppressor involved in apoptosis induction through TNFα . It has been reported that there was SRBC hyper methylation in Iranian GC tissues compared with normal margins which was significantly correlated with the age of patients . Adiponectin is a tumor suppressor that regulates apoptosis by the caspases and BCL2 activations [21, 22]. It has been observed that there were significantly higher expression levels of adiponectin receptors (AdipoR1 and AdipoR2) in a subpopulation of Iranian GC patients .
Micro RNAs and Long non-coding RNAs
MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the most popular non-coding RNAs associated with tumorigenesis. MicroRNAs negatively regulate the mRNAs through binding with ́three untranslated regions . These non-coding RNAs are involved in cell proliferation and migration through a post-transcriptional regulation of target mRNAs. MiR-21 is associated with cell growth, angiogenesis, and metastasis by targeting PTEN, APAF1, and TGF-β [25, 26]. MiR-146a is upregulated by inflammatory cytokines such as IL-1 and TNFα . STAT1, CCL8, and TLR4 are also the targets of miR-146a [28,29,30]. It has been shown that there were miR-19 and miR-21 over-expressions and miR-146, miR-375, and let-7 under-expressions in a subpopulation of Iranian GC patients . Another report has been also shown the miR-146a upregulation in primary stages of GC tumors among a group of Iranian cases . PTEN and RECK tumor suppressors are the targets of miR-222 [33, 34]. It has been observed that there were significantly increased miR-21 and miR-222 plasma levels in a sample of Iranian GC patients compared with controls. Therefore, these markers can be introduced as a minimally invasive diagnostic method for GC . FOXO3 transcription factor is one of the main miR-25 target genes which regulates cell cycle progression and apoptosis . MiR-106b/miR-93 functions as an oncogenic cluster through the regulation of p21 and BIM tumor suppressors . It has been observed that there were increased levels of miR-21, miR-25, miR-93, and miR-106b expressions in GC compared with normal samples among a group of Iranian cases. Except for the miR-93, over-expression of three other markers were significantly correlated with stage, H. pylori infection, and lymph node involvement. Since there were significant different miR-25 expressions between dysplasia and tumor tissues, the miR-25 can be introduced as a diagnostic marker for the early detection of GC . It has been also observed that there were significantly increased serum levels of miR-17 and miR-25, whereas the reduced levels of miR-133b expression among a subpopulation of Iranian GC patients compared with controls. MiR-17 and miR-25 were introduced as diagnostic markers of early tumor stages . Another group has been reported that there were significant decreased expression of miR-155-5p, miR-15a, and miR-186 in GC compared with controls among a group of Iranian cases. The H. pylori-positive GC tissues had lower levels of miR-155 in comparison with the infection-free samples. Moreover, the tumors with metastatic lymph nodes had significantly lower levels of miR-155 and miR-186 expressions . MiR-194 functions as a tumor suppressor via the regulation of NFAT5 and RAC1. MiR-210 is also another tumor suppressor which can inhibit the E2F3 expression. It has been shown that there were significantly lower levels of plasma miR-107, miR-194, and miR-210 expressions in a sample of Iranian intestinal-type GC cases compared with the control group . As a tumor suppressor, miR-124-3p targets the FRA2 and DNM3B. MiR-218-5p is also associated with CD44-ROCK signaling inhibition. Moreover, miR-484 suppresses cell proliferation and EMT process through downregulation of ZEB1 and SMAD2. It has been observed that there were miR-124-3p, miR-218-5p, and miR-484 downregulations in a group of Iranian GC cases. There was a significant correlation between miR-218 downregulation and advanced tumor grade. MiR-484 was correlated with malignant tumors in which advanced stage tumors had reduced levels of miR-484 expression . MiR-584 induces the EMT process through FOXA1 targeting . There was a significant miR-584 upregulation in gastric tumor tissues compared with normal margins among Iranian GC patients. There was a direct correlation between miR-584 upregulation and H. pylori infection. Moreover, miR-584 expression was inversely associated with higher stages and lymph node involvement .
LncRNAs are a class of non-coding RNAs with greater than 200 nucleotides in length [45, 46]. They have fundamental roles in cell differentiation, immune responses, and tumor progression through transcriptional and post-transcriptional mechanisms [47,48,49,50]. Since ncRNAs deregulations are associated with tumor progression, they can be used as diagnostic tumor markers . PlncRNA-1 is an lncRNA encoded by the CBR3 antisense, which is upregulated in different solid tumors [52, 53]. PlncRNA-1 upregulation was reported in a subpopulation of Iranian GC cases. There were significant correlations between PlncRNA-1 upregulation and sex, N-classification, and poor prognosis. PlncRNA-1 was introduced as a marker of GC progression among Iranian patients . RAB6C-AS1 expression was also assessed in a sample of Iranian GC patients that showed a probable association between RAB6C-AS1 and cell dedifferentiation during GC progression . ANRIL is an lncRNA associated with polycomb repressive components such as CBX7 and SU12. ANRIL downregulates the p16 and p15 through PRC1 and PRC2 [56, 57]. ANRASSF1 is a lincRNA transcribed from the opposite strand of RASSF1A gene which inhibits the RASSF1 expression through SUZ12 to promote cell proliferation . It has been reported that there were significant ANRIL and ANRASSF1 upregulations in a sample of Iranian GC patients . BC032913 is an lncRNA transcribed from the antisense strand of DPP10 which functions through recruitment of PRC2 complex. It has been observed that there was BC032913 downregulation in a sample of Iranian GC patients .
Signaling pathways and transcriptional regulation
There are various intra-extra cellular signaling networks that are involved in the biology of cells. These signaling pathways are the regulators of various cellular functions such as cell division, proliferation, apoptosis, and differentiation. Therefore, it is required for the normal cells to regulate the signaling pathways. Indeed, every aberration can result in deregulation of cellular hemostasis and neoplastic transformation. WNT signaling pathway regulates different developmental processes such as cell proliferation and migration . Therefore, deregulation of WNT pathway induces tumor progression through excessive cell proliferation . Catenin beta interacting protein 1 (CTNNBIP1) is an antagonist of β-catenin to bind with TCF/LEF complex . It has been reported that there was a significant CTNNBIP1 downregulation in tumors compared with normal margins among a sample of Iranian GC patients. Moreover, there was a significant correlation between the levels of CTNNBIP1 expression and sex in which the females had lower levels of CTNNBIP1 expression in comparison with males. A significant CTNNBIP1 under-expression was also observed in well-differentiated tumors that suggested the CTNNBIP1 as a tumor suppressor during tumor initiation .
Notch is a developmental signaling pathway involved in cell proliferation, differentiation, apoptosis, and self-renewal. It can be triggered by four Notch receptors (Notch1-4) following the ligand–receptor binding which results in cleavage of Notch intracellular domain (NICD) and nucleus translocation where it regulates the expression of target genes [65, 66]. GATA is a developmental transcription factor that activates canonical WNT signaling pathway during tumor progression . CDX2 is also a critical transcription factor involved in intestinal epithelial cells differentiation and proliferation . It has been reported that downregulation of Notch1 was correlated with distant metastases in a sample of Iranian GC patients. There was also a significant GATA6 downregulation in tumor samples compared with normal margins. A significant positive association was also observed between the levels of CTNNB1 and GATA6 expressions in GC tissues .
The cylindromatosis (CYLD) is a negative regulator of several signaling pathways such as WNT, SHH, and NOTCH, which have critical roles in apoptosis and cell cycle regulation. Therefore, CYLD aberration can be correlated with tumor progression [70, 71]. CYLD promoter methylation was assessed and showed that there was a significant correlation between CYLD under-expression and high-grade tumors, age, and sex. Moreover, CYLD under-expression was significantly correlated with lack of lymph node metastasis in Iranian GC cases .
The Hippo signaling pathway is involved in regulation of the cell proliferation and organ size . FAT4 belongs to the E-cadherin protein family and is also a member of Hippo signaling pathway which is involved in organ size. The (YAP/TAZ) transcriptional coactivator is the main component of hippo pathway to regulate cell proliferation [74, 75]. It has been observed that there was an inverse correlation between FAT4 expression and tumor grade among Iranian GC patients .
PI3K/AKT signaling pathway is also the regulator of different cellular processes that can be suppressed by PTEN. More than 30 AKT substrates have been reported that mediate the AKT functions in cell proliferation, differentiation, and migration. Therefore, aberrant PI3K/PTEN/AKT pathway can be observed in neoplastic transformation . UCA1 functions as a mediator of AKT pathway in activation of CREB transcription factor during tumorigenesis . UCA1 also upregulates the cyclin D1 which induces cell cycle progression in GC . Extra coding CEBPA (ecCEBPA) is an lncRNA that is involved in DNA methylation through interaction with DNA methyltransferase 1. Patterns of UCA1 and ecCEBPA expressions were assessed in a subpopulation of Iranian GC patients that showed ecCEBPA and UCA1 over-expressions in tumor tissues compared with normal margins. Moreover, the levels of UCA1 expressions were significantly correlated with tumor type and grade. Therefore, UCA1 and ecCEBPA were involved in GC and introduced as efficient diagnostic/prognostic markers in Iranian patients .
EGFR family of tyrosine kinase receptors is comprised of ERBB1-4 which are associated with cell proliferation, differentiation, and migration. EGFR activation triggers PI3K/AKT signaling pathway. The correlation between EGFR and ERBB3 expressions were assessed among a sample of Iranian GC cases which showed that the EGFR and ERBB3 co-overexpression was a poor prognostic marker. EGFR and ERBB3 co-overexpression was correlated with age and tumor size. It was concluded that the ERBB1/3 had a key role in the early stages of GC and can be suggested as diagnostic markers for the early detection of aggressive gastric tumors in this population . K-RAS is a G-protein member of RAS family involved in EGFR signaling pathway . A mutational analysis was performed to assess the frequency of KRAS codon 12 and 13 mutations in a sample of Iranian GC patients compared with the general population. Point mutations were observed among 30% of GC subjects. There was also a significant correlation between KRAS mutation and tumor location in which the majority of KRAS mutation codon 13 were in fundus .
Gastrokine 1 and 2 (GKN1 and 2) are mainly expressed in normal gastric epithelium and preserve the integrity of gastric mucosa . GKN1 induces apoptosis and reduces cell proliferation and epigenetic modification through the suppression of DNMT1, EZH2, and DNMT1. GKN2 inhibits the JAK2/STAT3 signaling pathway which results in reduced cell proliferation and apoptosis induction via upregulation of Bax and downregulation of Bcl-2 and Cyclin D1 . It has been reported that there was GKN1 downregulation in a sample of Iranian GC tissues .
RNA editing is a critical post-transcriptional process catalyzed by adenosine deaminase (ADAR) to change RNA molecules through adenosine deamination . It has been shown that there was significant ADAR over-expression in a sample of Iranian GC tumors which was significantly correlated with stage, poor prognosis, and tumor size. Tumors in stage IV had higher levels of ADAR expression compared with stage III . Piwi proteins are pivotal factors in genetic stability during spermatogenesis through suppression of retrotransposon. MAEL is a cancer testis and PIWI-interacting protein involved in transcriptional regulation of transposable elements and DNA damage . It has been reported that there was a correlation between MAEL expression and tumor sizes in Iranian GC patients. Higher levels of MAEL expression were observed in H. pylori positive in comparison with negative tumors. MAEL had higher levels of expression in primary-stage tumors which was directly correlated with lymph node metastasis . Androgen receptor (AR) belongs to the nuclear receptor family . There was AR over-expression in the majority of Iranian GC patients compared with normal cases which was positively correlated with increased lymph node involvement, tumor size, higher distant metastasis, and advanced stages .
The inflammatory cytokines are important components of the tumor microenvironment. Local inflammatory condition is prerequisite for the neoplastic transformation in some tumor types, whereas in other types the tumor cells change their local inflammatory condition to promote tumor progression. Therefore, identification of new molecular cancer-related inflammatory pathways prepares novel diagnostic modalities . NOD1 and NOD2 are members of NOD-like receptors (NLRs) family which are involved in gram-negative bacteria detection and chronic inflammatory response [94, 95]. They also stimulate the tumor progression through several transcription factors such as (NF)-κB and STAT1 . It has been shown that the Iranian GC cases had higher levels of NOD1 expression compared with the peptic ulcer disease (PUD) and non-ulcer dyspepsia (NUD) cases independent of H. pylori infection. PUD cases had also higher levels of NOD1 in comparison with the NUD cases. However, H. pylori-positive GC patients had higher levels of NOD2 expression compared with NUD and PUD groups .
Tim-3 is a regulator of anti-tumor immunity which is mainly expressed on Th1 cells, cytotoxic T-cells, and innate immune cells [98, 99]. Tim-3 expression in tumor infiltrating lymphocytes is correlated with TNF-a, IL-2, and IFN-γ aberration . Levels of Tim-3 mRNA and protein expressions were assessed in a subpopulation of Iranian GC and PUD cases. There was a significant Tim-3 upregulation among GC and PUD subjects in comparison with the controls. A probable role of Tim-3 was suggested in immunoregulatory mechanisms during the primary steps of GC or PUD progression .
IL-6 is a pro-inflammatory cytokine involved in the differentiation of immune system, bone metabolism, CRP synthesis, and tumor progression [102,103,104]. Role of IL-6 -174 G/C polymorphism in GC susceptibility was also evaluated among a subpopulation of Iranian patients. It was observed that there was a significant difference in G allele frequency between the controls and patients. Moreover, IL-6 -174 C/G polymorphism had a probable influence on GC susceptibility among the Iranian population .
VEGF family including VEGF-A to F are glycoproteins that are involved in tumor metastasis and angiogenesis . VEGF-A and B have key functions in blood vessels, whereas VEGF-C and D are involved in growth of lymphatic vessels [107, 108]. Inflammatory cytokines such as IL-1, IL-6, and TNF-α induce the VEGF that is responsible for tumor angiogenesis. Increased levels of VEGF-A and C expressions were observed among PUD or GC in comparison with NUD cases. Moreover, H. pylori positive PUD or GC cases had higher levels of VEGF-A and VEGF-C expressions compared with the negative cases. Therefore, VEGF-C over-expression following the inflammation can be resulted in neoplastic transformation of gastric mucosa into GC among Iranian patients .
IL-16 is a proinflammatory cytokine involved in immune system homeostasis, cell differentiation, and tumorigenesis [110, 111]. This factor can induce tumor-related cytokines such as TNF-α, IL-1β, IL-6, and IL-15 . It has been found that there was a significant correlation between rs1131445 T/C and rs4072111 T/C polymorphisms of IL-16 and GC susceptibility among Iranian population . IL-17 is a pro-inflammatory cytokine that is mainly produced by Th17 cells and is involved in innate and adaptive immune responses [114, 115]. Role of the IL-17 G-197A promoter polymorphism was assessed among a subpopulation of Iranian GC cases. There was a significantly higher frequency of G-197A polymorphism in GC compared with control subjects. There was also a significant correlation between -197A allele and tumor stages of I/II .
H. pylori is one of the most important factors in GC progression and activates pro-inflammatory cytokines [117, 118]. NO is a tumor-related proinflammatory factor which is upregulated following the H. pylori infection . It has been observed that there was a significant correlation between H. pylori infection and iNOS C150T polymorphism among Iranian GC patients in which, CT or TT iNOS genotypes increased the risk of GC progression in H. Pylori positive cases .
IL-1 is involved in chronic intestinal inflammation and tumor progression . It has been reported that there were significantly different frequencies of A1/A2 genotypes in IL-1RN VNTR polymorphism between tumor and control groups among a subpopulation of Iranian GC patients. Moreover, the ILRN *2/*2 genotype was correlated with high risk of GC in this population . CD40 belongs to the tumor necrosis factor protein family that functions in B cells maturation and maturation of antigen-presenting cells (APCs) for anti-tumor immunity. CD40/CD40L interaction inhibits tumor cell growth and induces apoptosis. It has been reported that there was CD40 hyper methylation in precancerous samples compared with normal tissues among Iranian GC patients which was associated with longer survival .
Stemness and self-renewal
Stemness and self-renewal are the ability of a cell to generate its lineage and differentiated cells which are observed in somatic and cancer stem cells (CSCs). CSCs are a subpopulation of tumor cells with self-renewal ability and resistance toward the chemotherapeutic treatments . CDX2 is a member of Homeobox transcription factors which is associated with cell differentiation, embryogenesis, tumorigenesis, and digestive disorders [125, 126]. CDX2 methylation status was evaluated in a subpopulation of Iranian GC cases that showed a significantly reduced CDX2 methylation in tumors compared with normal tissues . Olfactomedin 4 (OLFM4) is an important factor in neural crest development, cell cycle regulation, and tumorigenesis . NFk B and AP-1 are the upstream regulators of OLFM4 expression . OLFM4 over-expression has been observed in tumor tissues in comparison with the normal margins. Therefore, OLFM4 was suggested as an early diagnostic and stage-dependent prognostic marker among the Iranian GC patients . ZFX is a zinc-finger developmental transcriptional regulator . Levels of ZFX mRNA expression were assessed in a group of Iranian GC patients. It was shown that there were significantly different expression levels between different tumor types and grades, in which diffused types and advanced grade (III) tissues had higher levels of ZFX expressions . Another report evaluated the correlation between clinicopathological features and ZFX isoform 3/variant 5 expressions in Iranian GC samples. Although there was a heterogeneous pattern of expression among the patients, the majority of overexpressed cases were high-grade and diffuse-type. Moreover, there was a direct correlation between size of tumor and ZFX isoform 3/variant 5 mRNA expressions (132). CXCR4 as a G-coupled receptor has a key function in hematopoietic stem cells maintenance inside the bone marrow . Although, normal solid tissues have low levels of CXCR4 or lack of its expression, the majority of primary GC tissues had cytoplasmic and nucleus CXCR4 expressions. There was a correlation between CXCR4 expression and survival, in which the Iranian GC patients with positive CXCR4 nucleus expression had higher survival rates . PAX genes are tissue-specific transcription factors associated with developmental programs and cell differentiation . It has been shown that there was a lower level of circulating PAX5 expression in a subpopulation of Iranian GC patients compared with controls. Since 28% of patients were methylated and there was not any methylated sample among the normal cases, reduced levels of expression can be associated with PAX5 promoter methylation. Moreover, there were significant associations between PAX5 expression, age, and methylation status .
Cell adhesion and structural factors
Cell adhesion is a pivotal cellular process involved in cell polarity and tissue homeostasis. Reduced adhesive properties of tumor cells and subsequent signaling pathways are associated with tumor progression. Lack of cell–cell connections results in tumor metastasis. Cadherin-1 (CDH1) as a trans-membrane glycoprotein and tumor suppressor plays important roles in intercellular adhesion and normal-neoplastic morphogenesis [137, 138]. It was shown that there was not any correlation between CDH1 -160(C/A) polymorphism and GC susceptibility; however, CC genotype carriers had higher survival rates in comparison with the cases with CA genotype. Therefore, the CC genotype of CDH1 was suggested as a good prognostic marker among a subpopulation of Iranian GC patients .
HS3ST2 is involved in heparan sulfate biosynthesis via modification of glycosaminoglycan chains . It has been reported that there were CDH11 and HS3ST2 promoters hyper methylation in a sample of Iranian GC patients compared with controls . CD44 is one of the main factors in cellular connections, migration, and proliferation . CD44 activation increases cell proliferation and maintenance through PI3K/AKT signaling pathway . CD44 interaction with hyaluronan initiates tumorigenesis via regulation of cell growth, differentiation, and migration. It has been reported that there was a correlation between CD44 rs187116 polymorphism and survival of Iranian GC patients. CD44 polymorphisms can be used in early detection of patients with a high risk for tumor relapse . Another study showed a correlation between rs8193 C allele of CD44 and higher risk of GC among Iranian cases. The rs8193 C allele was also associated with increased lymph node involvement .
Mucin 1 (MUC1) is a membrane-bound glycoprotein involved in the protection of gastrointestinal epithelium toward microorganisms and enzymes . It has been reported that there was a significant correlation between rs4072037 AG genotype of MUC1 and reduced risk of GC among Iranian patients .
Actin filament-associated protein 1 (AFAP1) regulates the function of actin filaments which is associated with cell migration and metastasis . The AFAP1-antisense RNA 1 (AS1) is also an lncRNA transcribed from the antisense strand of AFAP1 . The AFAP1 and AFAP1-AS1 downregulations were observed in a subpopulation of Iranian GC subjects. There were also significant correlations between the levels of AFAP1 and AFAP1-AS1 expressions and tumor location in which the cardia tumors had decreased levels of expressions. Moreover, the younger patients and high-grade tumors had lower levels of AFAP1 expressions compared with older patients and low-grade tumors, respectively .
Actin is the basic factor of cellular motility during tumor progression and metastasis which is regulated by CFL1 . CFL1 induces the cell mobility through actin depolymerization . It is also activated through slingshot diphosphatase (SSH) . Therefore, SSH1 has a critical role in the regulation of cell migration . It has been reported that there was a significant correlation between SSH1 expression and cancerous nature of tumors which can be suggested as an efficient diagnostic marker of GC in Iranian population .
Beta-secretase 1 (BACE1) is a protease involved in myelin sheaths construction and amyloid-β peptides production [156, 157]. The BACE1 inhibitors reduce endothelial cell proliferation and tumor growth . It has been shown that there was significant BACE1 downregulation in a sample of Iranian GC patients which was associated with cardia region . Gelsolin (GSN) and Scinderin are important regulators of actin reorganization, cell motility, and morphology [160, 161]. It has been observed that there was a significant correlation between grade, age, and the levels of Gelsolin expression. A significant correlation was also between the levels of Scinderin expression and tumor size. Moreover, Gelsolin downregulation and Scinderin upregulation were associated with lymph node involvement among a sample of Iranian GC patients .
In the present review, we summarized all of the reported markers until now among Iranian GC patients. Regarding the different categories, it seems that the epigenetic modifications through non-coding RNAs are the main molecular processes involved in tumor initiation and progression among Iranian GC patients. Aberrant immune responses and inflammatory reactions had also pivotal roles in GC progression in this population. Indeed this review paves the way for introducing a specific panel of diagnostic markers for the Iranian population.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
AFAP1-antisense RNA 1
Actin filament-associated protein 1
Cancer stem cells
Catenin beta interacting protein 1
Cyclin-dependent kinase inhibitors
Extra coding CEBPA
- GKN1 and 2:
Gastrokine 1 and 2
Long non-coding RNAs
Peptic ulcer disease
Sadjadi A, Nouraie M, Mohagheghi MA, Mousavi-Jarrahi A, Malekezadeh R, Parkin DM (2005) Cancer occurrence in Iran in 2002, an international perspective. Asian Pacific J Cancer Prev APJCP 6(3):359–363
Wagner AD, Schneider PM, Fleig WE (2006) The role of chemotherapy in patients with established gastric cancer. Best Pract Res Clin Gastroenterol 20(4):789–799
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127(12):2893–2917
Forman D, Burley VJ (2006) Gastric cancer: global pattern of the disease and an overview of environmental risk factors. Best Pract Res Clin Gastroenterol 20(4):633–649
Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics, 2014. CA Cancer J Clin 64(1):9–29.
Pharoah PD, Dunning AM, Ponder BA, Easton DF (2004) Association studies for finding cancer-susceptibility genetic variants. Nat Rev Cancer 4(11):850–860
Malekzadeh R, Derakhshan MH, Malekzadeh Z (2009) Gastric cancer in Iran: epidemiology and risk factors. Arch Iran Med 12(6):576–583
Marin JJ, Al-Abdulla R, Lozano E, Briz O, Bujanda L, Banales JM et al (2016) Mechanisms of resistance to chemotherapy in gastric cancer. Anticancer Agents Med Chem 16(3):318–334
Park JH, Park J, Choi JK, Lyu J, Bae MG, Lee YG et al (2011) Identification of DNA methylation changes associated with human gastric cancer. BMC Med Genomics 4:82
Katai H, Ishikawa T, Akazawa K, Isobe Y, Miyashiro I, Oda I et al (2018) Five-year survival analysis of surgically resected gastric cancer cases in Japan: a retrospective analysis of more than 100,000 patients from the nationwide registry of the Japanese Gastric Cancer Association (2001–2007). Gastric Cancer 21(1):144–154
Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, Polkowski WP (2018) Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res 10:239–248
Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F (2014) Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomark Prev 23(5):700–713
Park MT, Lee SJ (2003) Cell cycle and cancer. J Biochem Mol Biol 36(1):60–65
Sherr CJ (2000) The Pezcoller lecture: cancer cell cycles revisited. Can Res 60(14):3689–3695
Abbaszadegan MR, Moaven O, Sima HR, Ghafarzadegan K, A’Rabi A, Forghani MN et al (2008) p16 promoter hypermethylation: a useful serum marker for early detection of gastric cancer. World J Gastroenterol 14(13):2055–2060
Moghbeli M, Moaven O, Dadkhah E, Farzadnia M, Roshan NM, Asadzadeh-Aghdaee H et al (2011) High frequency of microsatellite instability in sporadic colorectal cancer patients in Iran. Genetics Mol Res GMR 10(4):3520–3529
Moghbeli M, Moaven O, Memar B, Raziei HR, Aarabi A, Dadkhah E et al (2014) Role of hMLH1 and E-cadherin promoter methylation in gastric cancer progression. J Gastrointest Cancer 45(1):40–47
Azarhoush R, Keshtkar AA, Amiriani T, Kazemi-Nejad V (2008) Relationship between p53 expression and gastric cancers in cardia and antrum. Arch Iran Med 11(5):502–506
Lee JH, Kang MJ, Han HY, Lee MG, Jeong SI, Ryu BK et al (2011) Epigenetic alteration of PRKCDBP in colorectal cancers and its implication in tumor cell resistance to TNFalpha-induced apoptosis. Clin Cancer Res 17(24):7551–7562
Rezaei S, Hosseinpourfeizi MA, Moaddab Y, Safaralizadeh R (2020) Contribution of DNA methylation and EZH2 in SRBC down-regulation in gastric cancer. Mol Biol Rep 47(8):5721–5727
Brakenhielm E, Veitonmaki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B et al (2004) Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci USA 101(8):2476–2481
Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N et al (2000) Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96(5):1723–1732
Kordafshari M, Nourian M, Mehrvar N, Jalaeikhoo H, Etemadi A, Khoshdel AR et al (2020) Expression of AdipoR1 and AdipoR2 and serum level of adiponectin in gastric cancer. Gastrointestinal tumors 7(4):103–109
Nana-Sinkam SP, Croce CM (2013) Clinical applications for microRNAs in cancer. Clin Pharmacol Ther 93(1):98–104
Lu Z, Liu M, Stribinskis V, Klinge CM, Ramos KS, Colburn NH et al (2008) MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene 27(31):4373–4379
Wang Y, Lee CG (2009) MicroRNA and cancer–focus on apoptosis. J Cell Mol Med 13(1):12–23
Sheedy FJ, O’Neill LA (2008) Adding fuel to fire: microRNAs as a new class of mediators of inflammation. Ann Rheumat Dis 67 Suppl 3:iii50–iii55
Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T et al (2010) Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142(6):914–929
Rom S, Rom I, Passiatore G, Pacifici M, Radhakrishnan S, Del Valle L et al (2010) CCL8/MCP-2 is a target for mir-146a in HIV-1-infected human microglial cells. FASEB J 24(7):2292–2300
Yang K, He YS, Wang XQ, Lu L, Chen QJ, Liu J et al (2011) MiR-146a inhibits oxidized low-density lipoprotein-induced lipid accumulation and inflammatory response via targeting toll-like receptor 4. FEBS Lett 585(6):854–860
Ranjbar R, Hesari A, Ghasemi F, Sahebkar A (2018) Expression of microRNAs and IRAK1 pathway genes are altered in gastric cancer patients with Helicobacter pylori infection. J Cell Biochem 119(9):7570–7576
Adami B, Tabatabaeian H, Ghaedi K, Talebi A, Azadeh M, Dehdashtian E (2019) miR-146a is deregulated in gastric cancer. J Cancer Res Ther 15(1):108–114
Ge H, Cao YY, Chen LQ, Wang YM, Chen ZF, Wen DG et al (2008) PTEN polymorphisms and the risk of esophageal carcinoma and gastric cardiac carcinoma in a high incidence region of China. Dis Esophagus 21(5):409–415
Liu W, Song N, Yao H, Zhao L, Liu H, Li G (2015) miR-221 and miR-222 simultaneously target RECK and regulate growth and invasion of gastric cancer cells. Med Sci Monitor Int Med J Exp Clin Res 21:2718–2725
Emami SS, Nekouian R, Akbari A, Faraji A, Abbasi V, Agah S (2019) Evaluation of circulating miR-21 and miR-222 as diagnostic biomarkers for gastric cancer. J Cancer Res Ther 15(1):115–119
Yuan C, Wang L, Zhou L, Fu Z (2014) The function of FOXO1 in the late phases of the cell cycle is suppressed by PLK1-mediated phosphorylation. Cell Cycle 13(5):807–819
Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I et al (2008) E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 13(3):272–286
LArki P, Ahadi A, Zare A, Tarighi S, Zaheri M, Souri M et al (2018) Up-regulation of miR-21, miR-25, miR-93, and miR-106b in Gastric Cancer. Iran Biomed J 22(6):367–373
Zia Sarabi P, Sorayayi S, Hesari A, Ghasemi F. Circulating microRNA-133, microRNA-17 and microRNA-25 in serum and its potential diagnostic value in gastric cancer. J cell Biochem. 2019;120(8):12376–81.
Zare A, Alipoor B, Omrani MD, Zali MR, Alamdari NM, Ghaedi H. Decreased miR-155-5p, miR-15a, and miR-186 expression in gastric cancer is associated with advanced tumor grade and metastasis. Iran Biomed J. 2019;23(5):338.
Parvaee P, Sarmadian H, Khansarinejad B, Amini M, Mondanizadeh M (2019) Plasma level of MicroRNAs, MiR-107, MiR-194 and MiR-210 as potential biomarkers for diagnosis intestinal-type gastric cancer in human. Asian Pacific J Cancer Prevent APJCP 20(5):1421–1426
Zare A, Ahadi A, Larki P, Omrani MD, Zali MR, Alamdari NM et al (2018) The clinical significance of miR-335, miR-124, miR-218 and miR-484 downregulation in gastric cancer. Mol Biol Rep 45(6):1587–1595
Zhu Y, Jiang Q, Lou X, Ji X, Wen Z, Wu J et al (2012) MicroRNAs up-regulated by CagA of Helicobacter pylori induce intestinal metaplasia of gastric epithelial cells. PLoS ONE 7(4):e35147
Ebrahimi Ghahnavieh L, Tabatabaeian H, Ebrahimi Ghahnavieh Z, Honardoost MA, Azadeh M, Moazeni Bistgani M et al (2020) Fluctuating expression of miR-584 in primary and high-grade gastric cancer. BMC Cancer 20(1):621
Cao WJ, Wu HL, He BS, Zhang YS, Zhang ZY (2013) Analysis of long non-coding RNA expression profiles in gastric cancer. World J Gastroenterol 19(23):3658–3664
Crea F, Clermont PL, Parolia A, Wang Y, Helgason CD (2014) The non-coding transcriptome as a dynamic regulator of cancer metastasis. Cancer Metastasis Rev 33(1):1–16
Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D et al (2009) Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci USA 106(28):11667–11672
Nasrollahzadeh-Khakiani M, Emadi-Baygi M, Schulz WA, Nikpour P (2017) Long noncoding RNAs in gastric cancer carcinogenesis and metastasis. Brief Funct Genomics 16(3):129–145
Fatima R, Akhade VS, Pal D, Rao SM (2015) Long noncoding RNAs in development and cancer: potential biomarkers and therapeutic targets. Mol Cell Ther 3:5
Hajjari M, Salavaty A (2015) HOTAIR: an oncogenic long non-coding RNA in different cancers. Cancer Biol Med 12(1):1–9
Zeng MS (2016) Noncoding RNAs in cancer diagnosis. Adv Exp Med Biol 927:391–427
Jin Y, Cui Z, Li X, Jin X, Peng J (2017) Upregulation of long non-coding RNA PlncRNA-1 promotes proliferation and induces epithelial-mesenchymal transition in prostate cancer. Oncotarget 8(16):26090–26099
Yang Q, Cui ZL, Wang Q, Jin XB, Zhao Y, Wang MW et al (2017) PlncRNA-1 induces apoptosis through the Her-2 pathway in prostate cancer cells. Asian J Androl 19(4):453–457
Baratieh Z, Khalaj Z, Honardoost MA, Emadi-Baygi M, Khanahmad H, Salehi M et al (2017) Aberrant expression of PlncRNA-1 and TUG1: potential biomarkers for gastric cancer diagnosis and clinically monitoring cancer progression. Biomark Med 11(12):1077–1090
Salavaty A, Motlagh FM, Barabadi M, Cheshomi H, Esmatabadi MJD, Shahmoradi M, Soleimanpour-Lichaei HR. Potential role of RAB6C-AS1 long noncoding RNA in different cancers. J Cell Phys. 2019;234(1):891–903.
Kotake Y, Nakagawa T, Kitagawa K, Suzuki S, Liu N, Kitagawa M et al (2011) Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene 30(16):1956–1962
Yap KL, Li S, Munoz-Cabello AM, Raguz S, Zeng L, Mujtaba S et al (2010) Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell 38(5):662–674
Beckedorff FC, Ayupe AC, Crocci-Souza R, Amaral MS, Nakaya HI, Soltys DT et al (2013) The intronic long noncoding RNA ANRASSF1 recruits PRC2 to the RASSF1A promoter, reducing the expression of RASSF1A and increasing cell proliferation. PLoS Genet 9(8):e1003705
Kangarlouei R, Irani S, Noormohammadi Z, Memari F, Mirfakhraie R. ANRIL and ANRASSF1 long noncoding RNAs are upregulated in gastric cancer. J Cell Biochem. 2019;120(8):12544–8.
Behzadi S, Baradaran B, Hosseinpourfeizi MA, Dastmalchi N, Rajabi A, Asadi M, Safaralizadeh R. BC032913 as a novel antisense non-coding RNA is downregulated in gastric cancer. J Gastrointest Cancer. 2021;52(3):928–31.
Chiurillo MA (2015) Role of the Wnt/beta-catenin pathway in gastric cancer: An in-depth literature review. World journal of experimental medicine 5(2):84–102
Anastas JN, Moon RT (2013) WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 13(1):11–26
Gooding JM, Yap KL, Ikura M (2004) The cadherin-catenin complex as a focal point of cell adhesion and signalling: new insights from three-dimensional structures. BioEssays News Rev Mol Cell Dev Biol 26(5):497–511
Kosari-Monfared M, Nikbakhsh N, Fattahi S, Ghadami E, Ranaei M, Taheri H, Amjadi-Moheb F, Godazandeh GA, Shafaei S, Pilehchian-Langroudi M, Samadani AA, Akhavan-Niaki H. CTNNBIP1 downregulation is associated with tumor grade and viral infections in gastric adenocarcinoma. J Cell Physiol. 2019;234(3):2895–904.
Abbaszadegan MR, Riahi A, Forghanifard MM, Moghbeli M (2018) WNT and NOTCH signaling pathways as activators for epidermal growth factor receptor in esophageal squamous cell carcinoma. Cell Mol Biol Lett 23:42
Moghbeli M, Forghanifard MM, Sadrizadeh A, Mozaffari HM, Golmakani E, Abbaszadegan MR (2015) Role of Msi1 and MAML1 in regulation of notch signaling pathway in patients with esophageal squamous cell carcinoma. J Gastrointest Cancer 46(4):365–369
Zhong Y, Wang Z, Fu B, Pan F, Yachida S, Dhara M et al (2011) GATA6 activates Wnt signaling in pancreatic cancer by negatively regulating the Wnt antagonist Dickkopf-1. PLoS ONE 6(7):e22129
Zhang JF, Qu LS, Qian XF, Xia BL, Mao ZB, Chen WC (2015) Nuclear transcription factor CDX2 inhibits gastric cancercell growth and reverses epithelialtomesenchymal transition in vitro and in vivo. Mol Med Rep 12(4):5231–5238
Jafari N, Abediankenari S, Hosseini-Khah Z, Valizadeh SM, Torabizadeh Z, Zaboli E et al (2020) Expression patterns of seven key genes, including beta-catenin, Notch1, GATA6, CDX2, miR-34a, miR-181a and miR-93 in gastric cancer. Sci Rep 10(1):12342
Hellerbrand C, Bumes E, Bataille F, Dietmaier W, Massoumi R, Bosserhoff AK (2007) Reduced expression of CYLD in human colon and hepatocellular carcinomas. Carcinogenesis 28(1):21–27
Massoumi R (2010) Ubiquitin chain cleavage: CYLD at work. Trends Biochem Sci 35(7):392–399
Ghadami E, Nikbakhsh N, Fattahi S, Kosari-Monfared M, Ranaee M, Taheri H, Amjadi-Moheb F, Godazandeh G, Shafaei S, Nosrati A, Pilehchian Langroudi M. Epigenetic alterations of CYLD promoter modulate its expression in gastric adenocarcinoma: A footprint of infections. J Cell Physiol. 2019;234(4):4115–24.
Ehmer U, Sage J (2016) Control of proliferation and cancer growth by the hippo signaling pathway. Molecular cancer research : MCR 14(2):127–140
Ito T, Taniguchi H, Fukagai K, Okamuro S, Kobayashi A (2015) Inhibitory mechanism of FAT4 gene expression in response to actin dynamics during Src-induced carcinogenesis. PLoS ONE 10(2):e0118336
Jung HY, Cho H, Oh MH, Lee JH, Lee HJ, Jang SH et al (2015) Loss of FAT atypical cadherin 4 expression is associated with high pathologic T stage in radically resected gastric cancer. J Gastric Cancer 15(1):39–45
Pilehchian Langroudi M, Nikbakhsh N, Samadani AA, Fattahi S, Taheri H, Shafaei S et al (2017) FAT4 hypermethylation and grade dependent downregulation in gastric adenocarcinoma. J Cell Commun Signal 11(1):69–75
Kim D, Dan HC, Park S, Yang L, Liu Q, Kaneko S et al (2005) AKT/PKB signaling mechanisms in cancer and chemoresistance. Front Biosci 10:975–987
Yang C, Li X, Wang Y, Zhao L, Chen W (2012) Long non-coding RNA UCA1 regulated cell cycle distribution via CREB through PI3-K dependent pathway in bladder carcinoma cells. Gene 496(1):8–16
Wang ZQ, Cai Q, Hu L, He CY, Li JF, Quan ZW et al (2017) Long noncoding RNA UCA1 induced by SP1 promotes cell proliferation via recruiting EZH2 and activating AKT pathway in gastric cancer. Cell Death Dis 8(6):e2839
Nasrollahzadeh-Khakiani M, Emadi-Baygi M, Nikpour P (2017) Augmented expression levels of lncRNAs ecCEBPA and UCA1 in gastric cancer tissues and their clinical significance. Iran J Basic Med Sci 20(10):1149–1158
Moghbeli M, Makhdoumi Y, Soltani Delgosha M, Aarabi A, Dadkhah E, Memar B et al (2019) ErbB1 and ErbB3 co-over expression as a prognostic factor in gastric cancer. Biol Res 52(1):2
Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359(17):1757–1765
Ayatollahi H, Tavassoli A, Jafarian AH, Alavi A, Shakeri S, Shams SF et al (2018) KRAS Codon 12 and 13 Mutations in Gastric Cancer in the Northeast Iran. Iran J Pathol 13(2):167–172
Dai J, Zhang N, Wang J, Chen M, Chen J (2014) Gastrokine-2 is downregulated in gastric cancer and its restoration suppresses gastric tumorigenesis and cancer metastasis. Tumour Biol J Int Soc Oncodev Biol Med 35(5):4199–4207
Moss SF, Lee JW, Sabo E, Rubin AK, Rommel J, Westley BR et al (2008) Decreased expression of gastrokine 1 and the trefoil factor interacting protein TFIZ1/GKN2 in gastric cancer: influence of tumor histology and relationship to prognosis. Clin Cancer Res 14(13):4161–4167
Dokhaee F, Mazhari S, Galehdari M, Bahadori Monfared A, Baghaei K (2018) Evaluation of GKN1 and GKN2 gene expression as a biomarker of gastric cancer. Gastroenterol Hepatol Bed Bench 11(Suppl 1):S140–S145
Yang Y, Zhou X, Jin Y (2013) ADAR-mediated RNA editing in non-coding RNA sequences. Sci China Life Sci 56(10):944–952
Behroozi J, Shahbazi S, Bakhtiarizadeh MR, Mahmoodzadeh H (2020) ADAR expression and copy number variation in patients with advanced gastric cancer. BMC Gastroenterol 20(1):152
Soper SF, van der Heijden GW, Hardiman TC, Goodheart M, Martin SL, de Boer P et al (2008) Mouse maelstrom, a component of nuage, is essential for spermatogenesis and transposon repression in meiosis. Dev Cell 15(2):285–297
Abbaszadegan MR, Taghehchian N, Aarabi A, Moghbeli M (2020) MAEL cancer-testis antigen as a diagnostic marker in primary stages of gastric cancer with helicobacter pylori infection. J Gastrointest Cancer 51(1):17–22
Konduri S, Schwarz MA, Cafasso D, Schwarz RE (2007) Androgen receptor blockade in experimental combination therapy of pancreatic cancer. J Surg Res 142(2):378–386
Soleymani Fard S, Yazdanbod M, Sotoudeh M, Bashash D, Mahmoodzadeh H, Saliminejad K et al (2020) Prognostic and therapeutic significance of androgen receptor in patients with gastric cancer. Onco Targets Ther 13:9821–9837
Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454(7203):436–444
Girardin SE, Tournebize R, Mavris M, Page AL, Li X, Stark GR et al (2001) CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri. EMBO Rep 2(8):736–742
Strober W, Murray PJ, Kitani A, Watanabe T (2006) Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 6(1):9–20
Hirata Y, Ohmae T, Shibata W, Maeda S, Ogura K, Yoshida H et al (2006) MyD88 and TNF receptor-associated factor 6 are critical signal transducers in Helicobacter pylori-infected human epithelial cells. J Immunol 176(6):3796–3803
Mohammadian Amiri R, Tehrani M, Taghizadeh S, Shokri-Shirvani J, Fakheri H, Ajami A (2016) Association of nucleotide-binding oligomerization domain receptors with peptic ulcer and gastric cancer. Iran J Allergy Asthma Immunol 15(5):355–362
Anderson AC (2012) Tim-3, a negative regulator of anti-tumor immunity. Curr Opin Immunol 24(2):213–216
Gorman JV, Colgan JD (2014) Regulation of T cell responses by the receptor molecule Tim-3. Immunol Res 59(1–3):56–65
Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC (2010) Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 207(10):2187–2194
Naghavi-Alhosseini M, Tehrani M, Ajami A, Rafiei A, Taghvaei T, Vahedi-Larijani L et al (2017) Tim-3 up-regulation in patients with gastric cancer and peptic ulcer disease. Asian Pacific J Cancer Prevent APJCP 18(3):765–770
Galun E, Nahor O, Eid A, Jurim O, Rose-John S, Blum HE et al (2000) Human interleukin-6 facilitates hepatitis B virus infection in vitro and in vivo. Virology 270(2):299–309
Lu Y, Lu F, Zeng S, Sun S, Lu L, Liu L (2015) Genetics and gastric cancer susceptibility. Int J Clin Exp Med 8(6):8377–8383
Salgado R, Junius S, Benoy I, Van Dam P, Vermeulen P, Van Marck E et al (2003) Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int J Cancer 103(5):642–646
Attar M, Mansoori M, Shahbazi M (2017) Interleukin-6 genetic variation and susceptibility to gastric cancer in an Iranian population. Asian Pacific J Cancer Prevent APJCP 18(11):3025–3029
McColm JR, Geisen P, Hartnett ME (2004) VEGF isoforms and their expression after a single episode of hypoxia or repeated fluctuations between hyperoxia and hypoxia: relevance to clinical ROP. Mol Vis 10:512–520
de Paulis A, Prevete N, Fiorentino I, Rossi FW, Staibano S, Montuori N et al (2006) Expression and functions of the vascular endothelial growth factors and their receptors in human basophils. J Immunol 177(10):7322–7331
Yuanming L, Feng G, Lei T, Ying W (2007) Quantitative analysis of lymphangiogenic markers in human gastroenteric tumor. Arch Med Res 38(1):106–112
Taghizadeh S, Sankian M, Ajami A, Tehrani M, Hafezi N, Mohammadian R et al (2014) Expression levels of vascular endothelial growth factors a and C in patients with peptic ulcers and gastric cancer. J Gastric Cancer 14(3):196–203
Fina D, Pallone F (2008) What is the role of cytokines and chemokines in IBD? Inflamm Bowel Dis 14(Suppl 2):S117–S118
Yellapa A, Bahr JM, Bitterman P, Abramowicz JS, Edassery SL, Penumatsa K et al (2012) Association of interleukin 16 with the development of ovarian tumor and tumor-associated neoangiogenesis in laying hen model of spontaneous ovarian cancer. Int J Gynecol Cancer 22(2):199–207
Mathy NL, Scheuer W, Lanzendorfer M, Honold K, Ambrosius D, Norley S et al (2000) Interleukin-16 stimulates the expression and production of pro-inflammatory cytokines by human monocytes. Immunology 100(1):63–69
Kashfi SM, Behboudi Farahbakhsh F, Nazemalhosseini Mojarad E, Mashayekhi K, Azimzadeh P, Romani S et al (2016) Interleukin-16 polymorphisms as new promising biomarkers for risk of gastric cancer. Tumour Biol J Int Soc Oncodev Biol Med 37(2):2119–2126
Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517
Moseley TA, Haudenschild DR, Rose L, Reddi AH (2003) Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 14(2):155–174
Rafiei A, Hosseini V, Janbabai G, Ghorbani A, Ajami A, Farzmandfar T et al (2013) Polymorphism in the interleukin-17A promoter contributes to gastric cancer. World J Gastroenterol 19(34):5693–5699
Peek RM Jr, Blaser MJ (2002) Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer 2(1):28–37
Polk DB, Peek RM Jr (2010) Helicobacter pylori: gastric cancer and beyond. Nat Rev Cancer 10(6):403–414
Goto T, Haruma K, Kitadai Y, Ito M, Yoshihara M, Sumii K et al (1999) Enhanced expression of inducible nitric oxide synthase and nitrotyrosine in gastric mucosa of gastric cancer patients. Clin Cancer Res 5(6):1411–1415
Rafiei A, Hosseini V, Janbabai G, Fazli B, Ajami A, Hosseini-Khah Z et al (2012) Inducible nitric oxide synthetase genotype and Helicobacter pylori infection affect gastric cancer risk. World J Gastroenterol 18(35):4917–4924
Lopetuso LR, Chowdhry S, Pizarro TT (2013) Opposing functions of classic and novel IL-1 family members in gut health and disease. Front Immunol 4:181
Abbasian MH, Abbasi B, Ansarinejad N, Motevalizadeh Ardekani A, Samizadeh E, Gohari Moghaddam K et al (2018) Association of interleukin-1 gene polymorphism with risk of gastric and colorectal cancers in an Iranian population. Iran J Immunol IJI 15(4):321–328
Amini M, Ghorban K, Mokhtarzadeh A, Dadmanesh M, Baradaran B (2020) CD40 DNA hypermethylation in primary gastric tumors; as a novel diagnostic biomarker. Life Sci 254:117774
Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8(10):755–768
Camilo V, Barros R, Sousa S, Magalhaes AM, Lopes T, Mario Santos A et al (2012) Helicobacter pylori and the BMP pathway regulate CDX2 and SOX2 expression in gastric cells. Carcinogenesis 33(10):1985–1992
Qin R, Wang NN, Chu J, Wang X (2012) Expression and significance of homeodomain protein Cdx2 in gastric carcinoma and precancerous lesions. World J Gastroenterol 18(25):3296–3302
Samadani AA, Nikbakhsh N, Pilehchian M, Fattahi S, Akhavan-Niaki H (2016) Epigenetic changes of CDX2 in gastric adenocarcinoma. J Cell Commun Signal 10(4):267–272
Chin KL, Aerbajinai W, Zhu J, Drew L, Chen L, Liu W et al (2008) The regulation of OLFM4 expression in myeloid precursor cells relies on NF-kappaB transcription factor. Br J Haematol 143(3):421–432
Dabiri A, Baghaei K, Hashemi M, Sadravi S, Malekpour H, Habibi M et al (2017) Identification of differentially-expressed of Olfactomedin-related proteins 4 and COL11A1 in Iranian patients with intestinal gastric cancer. Gastroenterol Hepatol Bed Bench 10(Suppl1):S62–S69
Galan-Caridad JM, Harel S, Arenzana TL, Hou ZE, Doetsch FK, Mirny LA et al (2007) Zfx controls the self-renewal of embryonic and hematopoietic stem cells. Cell 129(2):345–357
Nikpour P, Emadi-Baygi M, Mohammad-Hashem F, Maracy MR, Haghjooy-Javanmard S (2012) Differential expression of ZFX gene in gastric cancer. J Biosci 37(1):85–90
Rahmati S, Emadi-Baygi M, Nikpour P, Emadi-Andani E (2014) Expression profile of ZFX isoform3/variant 5 in gastric cancer tissues and its association with tumor size. Iran J Basic Med Sci 17(10):767–771
Liekens S, Schols D, Hatse S (2010) CXCL12-CXCR4 axis in angiogenesis, metastasis and stem cell mobilization. Curr Pharm Des 16(35):3903–3920
Nikkhoo B, Jalili A, Fakhari S, Sheikhesmaili F, Fathi F, Rooshani D et al (2014) Nuclear pattern of CXCR4 expression is associated with a better overall survival in patients with gastric cancer. J Oncol 2014:808012
Balasenthil S, Gururaj AE, Talukder AH, Bagheri-Yarmand R, Arrington T, Haas BJ et al (2007) Identification of Pax5 as a target of MTA1 in B-cell lymphomas. Can Res 67(15):7132–7138
Haghverdi MK, Moslemi E (2018) Expression rate and PAX5 gene methylation in the blood of people suffering from gastric cancer. Open Access Macedonian J Med Sci 6(9):1571–1576
Beavon IR (2000) The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation. Eur J Cancer 36(13 Spec No):1607–1620
Fleming TP, Papenbrock T, Fesenko I, Hausen P, Sheth B (2000) Assembly of tight junctions during early vertebrate development. Semin Cell Dev Biol 11(4):291–299
Menbari MN, Nasseri S, Menbari N, Mehdiabadi R, Alipur Y, Roshani D (2017) The -160 (C>A) CDH1 gene promoter polymorphism and its relationship with survival of patients with gastric cancer in Kurdistan. Asian Pacific J Cancer Prevent APJCP 18(6):1561–1565
Hwang JA, Kim Y, Hong SH, Lee J, Cho YG, Han JY et al (2013) Epigenetic inactivation of heparan sulfate (glucosamine) 3-O-sulfotransferase 2 in lung cancer and its role in tumorigenesis. PLoS ONE 8(11):e79634
Eyvazi S, Khamaneh AM, Tarhriz V, Bandehpour M, Hejazi MS, Sadat ATE et al (2020) CpG islands methylation analysis of CDH11, EphA5, and HS3ST2 genes in gastric adenocarcinoma patients. J Gastrointest Cancer 51(2):579–583
Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4(1):33–45
Bourguignon LY, Zhu H, Chu A, Iida N, Zhang L, Hung MC (1997) Interaction between the adhesion receptor, CD44, and the oncogene product, p185HER2, promotes human ovarian tumor cell activation. J Biol Chem 272(44):27913–27918
Bitaraf SM, Mahmoudian RA, Abbaszadegan M, Mohseni Meybodi A, Taghehchian N, Mansouri A et al (2018) Association of two CD44 polymorphisms with clinical outcomes of gastric cancer patients. Asian Pacific J Cancer Prevent APJCP 19(5):1313–1318
Mokhtarian R, Tabatabaeian H, Saadatmand P, Azadeh M, Balmeh N, Yakhchali B et al (2020) CD44 Gene rs8193 C allele is significantly enriched in gastric cancer patients. Cell J 21(4):451–458
Brayman M, Thathiah A, Carson DD (2004) MUC1: a multifunctional cell surface component of reproductive tissue epithelia. Reproduct Biol Endocrinol RB&E 2:4
Alikhani R, Taravati A, Hashemi-Soteh MB (2020) Association of MUC1 5640G>A and PSCA 5057C>T polymorphisms with the risk of gastric cancer in Northern Iran. BMC Med Genet 21(1):148
Liu FT, Xue QZ, Zhu PQ, Luo HL, Zhang Y, Hao T (2016) Long noncoding RNA AFAP1-AS1, a potential novel biomarker to predict the clinical outcome of cancer patients: a meta-analysis. Onco Targets Ther 9:4247–4254
Zhao H, Zhang K, Wang T, Cui J, Xi H, Wang Y et al (2018) Long non-coding RNA AFAP1-antisense RNA 1 promotes the proliferation, migration and invasion of gastric cancer cells and is associated with poor patient survival. Oncol Lett 15(6):8620–8626
Esfandi F, Taheri M, Namvar A, Oskooei VK, Ghafouri-Fard S (2019) AFAP1 and its naturally occurring antisense RNA are downregulated in gastric cancer samples. Biomed Rep 10(5):296–302
Otterbein LR, Graceffa P, Dominguez R (2001) The crystal structure of uncomplexed actin in the ADP state. Science 293(5530):708–711
Bamburg JR, McGough A, Ono S (1999) Putting a new twist on actin: ADF/cofilins modulate actin dynamics. Trends Cell Biol 9(9):364–370
Wang W, Mouneimne G, Sidani M, Wyckoff J, Chen X, Makris A et al (2006) The activity status of cofilin is directly related to invasion, intravasation, and metastasis of mammary tumors. J Cell Biol 173(3):395–404
Nishita M, Wang Y, Tomizawa C, Suzuki A, Niwa R, Uemura T et al (2004) Phosphoinositide 3-kinase-mediated activation of cofilin phosphatase Slingshot and its role for insulin-induced membrane protrusion. J Biol Chem 279(8):7193–7198
Daryabari SS, Safaralizadeh R, Hosseinpourfeizi M, Moaddab Y, Shokouhi B (2018) Overexpression of SSH1 in gastric adenocarcinoma and its correlation with clinicopathological features. J Gastrointest Oncol 9(4):728–733
John V (2006) Human beta-secretase (BACE) and BACE inhibitors: progress report. Curr Top Med Chem 6(6):569–578
Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A et al (2006) Control of peripheral nerve myelination by the beta-secretase BACE1. Science 314(5799):664–666
Paris D, Quadros A, Patel N, DelleDonne A, Humphrey J, Mullan M (2005) Inhibition of angiogenesis and tumor growth by beta and gamma-secretase inhibitors. Eur J Pharmacol 514(1):1–15
Esfandi F, Ghafouri-Fard S, Oskooei VK, Taheri M. β-Secretase 1 and its naturally occurring anti-sense RNA are Down-regulated in gastric Cancer. Pathol Oncol Res. 2019;25(4):1627–33.
Shirkoohi R, Fujita H, Darmanin S, Takimoto M (2012) Gelsolin induces promonocytic leukemia differentiation accompanied by upregulation of p21CIP1. Asian Pacific J Cancer Prevent APJCP 13(9):4827–4834
Trifaro JM, Rose SD, Marcu MG (2000) Scinderin, a Ca2+-dependent actin filament severing protein that controls cortical actin network dynamics during secretion. Neurochem Res 25(1):133–144
Tavabe Ghavami TS, Irani S, Mirfakhrai R, Shirkoohi R (2020) Differential expression of Scinderin and Gelsolin in gastric cancer and comparison with clinical and morphological characteristics. EXCLI J 19:750–761
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Abbaszadegan, M.R., Mojarrad, M., Rahimi, H.R. et al. Genetic and molecular biology of gastric cancer among Iranian patients: an update. Egypt J Med Hum Genet 23, 17 (2022). https://doi.org/10.1186/s43042-022-00232-w
- Gastric cancer
- Risk factor