| Gastric cancer is one of the most common malignancies and second leading cause of cancer-related death worldwide. The intimate relationship between Helicobacter pylori infection and gastric cancer has long been established and it is proposed that Helicobacter pylori infection is involved in an early stage of gastric cancer pathogenesis by causing a chronic gastritis, the precursor to all the patho-physiologic abnormalities characteristic of gastric carcinogenesis. However, these pre-malignant lesions only develop in a proportion of infected subjects and do not necessarily progress into invasive cancers. The host genetic, bacterial virulence, environmental and many other factors are suggested to significantly affect the oncogenic process initiated by Helicobacter pylori infection, but the underlying molecular mechanism is largely unclear. Additionally, because of lacks of reliable early diagnostic markers and efficient intervention approaches, the prognosis of gastric cancer remains poor. Therefore, better defining the pathogenesis of gastric cancer, looking for useful biomarkers, and exploring novel therapeutic targets for treatment are urgently demanding tasks.A hallmark of cancers including gastric cancer is unlimited cellular proliferation due to the aberrant expression of key factors regulating cell proliferation and survival. Recent studies have shed light on cellular senescence, an irreversible cell growth arrest status, as a potent tumor suppression mechanism. Evidence has also accumulated that induction of senescence contributes to the treatment efficacy of chemotherapeutic agents and other anti-cancer strategies. It is known that activation of telomerase through induction of its rate-limiting component telomerase reverse transcriptase (hTERT) is a critical strategy that erases senescence barrier during malignant transformation. Moreover, functional inactivation of the tumor suppressors p53 and p16, the key regulators of cellular life-span, disrupts intrinsic senescence program, thereby contributing to the infinite proliferation potential of cancer cells at another layer. Despite such general knowledge, however, it remains incompletely understood how exactly sustained cancer cell proliferation is maintained and whether other oncogenic factors are involved in the prevention of senescence of gastric and other cancer cells. In this research, FoxM1 and RBP2 were selected to study the role of them in gastric cancer and the relation with cell senescence.The Forkhead Box M1 (FoxM1) transcription factor, a master regulator of mitotic gene expression, promotes the development and progression of several types of malignancies. In the present study, we determined the functional role of FoxM1 in gastric cancer cells and its expression in primary gastric cancers. FoxM1 was expressed in all examined gastric cancer cell lines and when it was knocked-down, impaired clonogenicity and cellular senescence occurred independently of p53 and p16 status. Following FoxM1 depletion, its target genes c-MYC and SKP2 were substantially down-regulated, which was coupled with the accumulation of the CDK inhibitor p27kip1. Importantly, the FoxM1 inhibition-mediated cellular senescence and clonogenic defect was substantially prevented by the abolishment of p27kip1 induction. Telomerase reverse transcriptase (hTERT), the key component of telomerase, a nucleoprotein enzyme essential for cellular immortalization, was also inhibited in the FoxM1-depleted gastric cancer cells. Moreover, the over-expression of FoxM1 was observed in 39 of 42 tumor specimens derived from patients with gastric cancer. Collectively, the FoxM1 gene is aberrantly activated in gastric cancer and is required for sustained proliferation of the cancer cells. The FoxM1 deficiency triggers p53 and p16-independent senescence of cancer cells by regulating the expression of p27kip1 and other targets. The findings provide mechanistic insights into roles of FoxM1 in pathogenesis of gastric cancer and FoxM1 may thus be implicated in the diagnosis and treatment of gastric cancer.The aberrant expression of histone-modifying enzyme has long been implicated in oncogenesis. However, it is unclear whether RBP2, a newly identified histone demethylase, involved in the pathogenesis of carcinoma including gastric cancer. We determined RBP2 expression in gastric cancer and its functional role in cancer cells. Cancerous and matched normal specimens from 42 patients with gastric cancer were analyzed for RBP2 expression using quantitative real-time PCR (QRT-PCR) and immunohistochemistry. RBP2 and other gene expression in cell lines was assessed using QRT-PCR and immunoblotting, and knocked down with specific small interference RNA. Clonogenesis and cellular senescence were determined using foci formation and Senescence associatedβ-Galactosidase staining. The promoter activity was determined by luciferase reporter assay. Chromatin immunoprecipitation was used to examine RBP2 and methylated histone H3-K4 on the target promoters. RBP2 mRNA and protein expression increased in 71.5% (30/42) and 100% (20/20) of primary gastric cancer specimens, respectively. Significantly diminished foci numbers coupled with massive senescence and elevated expression of the cyclin-dependent kinase inhibitors (CDKIs) p21CIP2, p27kip1 and/or p16ink4a, occurred in the RBP2 depleted gastric and cervical cancer cells. RBP2 knocking-down enhanced the promoter activity of all three CDKIs genes. RBP2 occupied these promoter regions in the control cells and the loss of RBP2 occupancy was accompanied by enhanced H3-K4 tri- methylation following RBP2 depletion.All the research showed FoxM1 and RBP2 is over-expressed in gastric cancer and their inhibition triggers senescence of malignant cells by derepressing the CDKI target genes. Cell senescence induced by FoxM1 inhibition and histone demethylase inhibition by targeting RBP2 may be the novel strategy against gastric cancer.
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