Identification Of Novel Diagnostic Markers And Therapeutic Targets For Gastric Cancer: With Emphasis On HTERT, CIP2A And JMJD2B

Gastric cancer is one of the most common malignancies worldwide, especially in China,and ranks second in terms of global cancer-related mortality.Better defining the molecular pathogenesis of gastric cancer, looking for useful diagnostic markers,and exploring novel therapeutic targets for treatment are thus urgently demanding tasks.To these ends, my thesis was designed to determine expression of telomerase,CIP2A and JMJD2B and evaluate their biological and clinical significances in gastric cancer.Activation of telomerase by the induction of a full-length telomerase reverse transcriptase(hTERT)transcript is a critical step during malignant transformation.Telomerase activity or hTERT expression has thus served as diagnostic and/or prognostic markers in certain human malignancies.We investigated the expression of hTERT in normal and malignant gastric tissues derived from 37 patients with gastric cancers. Overall hTERT mRNA was detectable in 33/37(90%)of tumour specimens and 23/37(62%)of the corresponding normal gastric tissues.Twenty-five of 37 tumours(71%)expressed the full-length hTERT mRNA,and unexpectedly, this full-length transcript was found in 16 of 37(43%)normal gastric tissues.Immunohistochemical analyses demonstrated a positive hTERT staining in small fractions of normal epithelial cells and in most gastric cancer cells.The finding that the full length hTERT transcript was present in both normal and malignant gastric tissues will preclude its use as a gastric cancer marker. CIP2A is the newly identified oncogenic factor stabilizing c-MYC protein and driving cellular transformation.We found that CIP2A mRNA was present in 34 of 37(90%)of tumor specimens whereas absent in 26 of 37 (70%)of matched normal gastric mucosa.A total of 32(87%)gastric cancer samples over-expressed CIP2A.CIP2A protein expression was readily detectable in the tumor tissues while absent in most normal gastric mucosa. Depleting CIP2A expression substantially inhibited growth and clonogenic capabilities of tumor cell lines independently of p53 and pRB pathways. Gastric cancer-derived AGS cells underwent senescence following the inhibition of CIP2A expression.Moreover,CIP2A depletion triggered partial differentiation of leukemic HL60 cells.Taken together,CIP2A in tumor cells is required for sustained proliferation by preventing cell growth arrest,senescence or differentiation;and it may serve as a diagnostic marker and therapeutic target for gastric cancer.JMJD2B is a bistone demethylase that regulates gene transcription via remodelling chromatin.Our preliminary data showed that the depletion of JMJD2B significantly inhibited the clonogenic capacity of a panel of gastric cancer cell lines including AGS,HGC-27,and BGC-823 through p53-dependent and independent pathways.The findings suggest that targeting JMJD2B may be a novel strategy against gastric cancer.To conclude,our findings indicate that(â…°)hTERT detection can't distinguish normal from cancerous gastric tissues;(â…±)CIP2A may serve as diagnostic and therapeutic molecules in gastric cancer;and(â…²) targeting JMJD2B may have therapeutic implications in gastric cancer.