| Gastric cancer remains the second leading cause of cancer-related mortalityworldwide. It is widely accepted that gastric carcinogenesis is a complex, multistepand multifactorial process involving genetic and epigenetic alteration ofprotein-coding protooncogenes and tumor-suppressor genes. Genetic polymorphismshave been considered as the main genetic elements involved in the development ofvarious diseases, including gastric cancer. Although the precise molecular mechanismremains unclear, genetic polymorphisms are thought to play important roles in gastriccarcinogenesis. Genetic factors of gastric cancer carcinogenesis, including oncogenes,tumor suppressor genes, apoptosis related genes and metastasis relatedgenes. Moreover, the forms of gene change are various. In the present study, we areparticularly focusing on the polymorphism of Janus kinase2(JAK2), which is amember of the family of tyrosine kinases (TKs).It has been shown that JAK2is closely associated with cancer proliferation,metastasis and epithelial mesenchymal transition (EMT). It was reported that JAK2was an oncogene and down-regulation of JAK2was found to significantly suppressthe proliferation of gastric cancer cells. The gene for JAK2is located onchromosome9p24.1. To date, several JAK2single nucleotide polymorphisms (SNPs)have been identified to be significantly associated with various diseases. Moreover,rs1887427is an upstream promoter’s SNP, which has significantly effects on theexpression of JAK2gene. However, to our knowledge, there is no study concerning the association between the functional polymorphism and susceptibility to gastriccancer. Thus, to evaluate the impact of the JAK2gene polymorphism on gastriccancer risk, we conducted a hospital-based case-control study including168gastriccancer patients and199age and gender matched control subjects. The genotypeswere identified by polymerase chain reaction-restriction fragment lengthpolymorphism (PCR-RFLP) methods. In our results, the frequencies of the wild andvariant genotypes in cases were significantly different from those of controls(P=0.027). Compared with individuals with the wild genotype AA, subjects with thevariant genotypes (AG+GG) had a significantly higher risk of gastric cancer(P=0.023, adjusted OR=1.71,95%CI=1.08-2.71). Moreover, individuals with theAG heterozygotes were also increased in the patients compared with the gastriccancer-free controls (P=0.018, adjusted OR=1.78,95%CI=1.10-2.87), but theassociation was not statistically significant in the GG homozygotes. Furthermore, instratified analyses, the elevated gastric cancer risk was especially evident in youngerindividuals, males and nonsmokers (P<0.05for all). Further analyses revealed thatthe variant genotypes were associated with tumor localization in the sub-analysis ofgastric cancer patients (P=0.017, adjusted OR=2.69,95%CI=1.20-6.06).In conclusions, the JAK2polymorphism may be not only associated with anincreased risk of gastric cancer but also with tumor localization in a Chinesepopulation. According to the study on gene polymorphism and gastric cancer risk,the results help us to have a deeper understanding of the etiology and pathogenesisof gastric cancer at the molecular level. In addition, it is important to find thepolymorphism which could be used as the marker for genetic susceptibility to gastriccancer and might be providing a novel and efficient way to prevent this disease. MicroRNAs (miRNAs), a class of small endogenous noncoding RNAs,19-25nucleotides in length，negatively regulate post-transcriptional gene expression bydirectly cleaving target mRNA or by inhibiting their translation. They have beenimplicated to regulate about30%human genes, and play crucial roles in manycelluar processes including cell proliferation, differentiation, apoptosis, and invasion.Rencently, accumulating evidence indicated that miRNAs function as an alternativemethod for cancer subtype classification and prognostication.Perifosine is an alkylphospholipid exhibiting antitumor activity as shown in bothpreclinical studies and clinical trials. Its anticancer activity is known to target cellmembrane, inhibit Akt and mTOR signaling, involving growth arrest, apoptosis andsurvival. In the preclinical studies, perifosine combined with UCN-1, etoposide andother antitumor agents shows synergistic antitumor effects. In the clinic trials,perifosine shows substantial antitumor activity in sarcoma and perhaps renal cellcarcinoma. To date, perifosine’s effects on gastric cancer are unknown.In the present study, we detected miR-27a expression in human gastric cancertissues and cell lines by quantitative RT-PCR. Moreover, we analyzed the correlationbetween miR-27a expression and clinicopathological characteristics of gastric cancer.We further explored the growth inhibitory effect of perifosine on human gastriccancer cells with or without co-targeting miR-27a by SRB assay. The results showedthat miR-27a expression was significantly up-regulated in gastric cancer tissues,compared with their non-tumor adjacent tissues. High expression levels of miR-27awere associated with poor tumor histological grade (P=0.037). MiR-27a inhibitorssuppressed the growth of MGC-803cells, in which miR-27a expression was high. Further research assays revealed that perifosine exerted its activity selectively onAGS cell line. The growth inhibitory effect of perifosine was enhanced significantlyin combination with miR-27a inhibitors in MGC-803cells and the possiblemechanism was down-regulating the MDR1gene P-glycoprotein expression.Taken together, our results demonstrate that miR-27a as an oncogene, may be apotential therapeutic target and prognostic factor in gastric cancer. MiR-27ainhibitors alone or in combination with perifosine may be a novel therapeuticapproach against gastric cancer. |
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