Junctophilin3, A Novel Methylation Controlled Tumor Suppressor Gene In Gastric And Colorectal Cancer

Gastric and colorectal cancers are among the most common cancers and causes of cancer mortality worldwide, while epigenetic disruption of tumor suppressor genes (TSGs) is a fundamental contributor to their pathogenesis.Purpose:We studied the inactivation of a novel candidate TSG JPH3through promoter methylation, and explored its functions and its mechanism in the pathogenesis of these cancers.Methods:JPH3methylation was evaluated by methylation-specific PCR and bisulfite genome sequencing. JPH3expression was determined by quantitative RT-PCR and immunohistochemistry. The effects of JPH3on the growth and migration of tumor cells were tested in vitro. Apoptosis, ER stress status, plasmic Ca2+and several signaling proteins were detected.Results:JPH3was methylated in most tumor cell lines with silenced or reduced expression, also in most tumors but not in any normal gastric or colonic mucosa tissue. While JPH3protein expression was high in normal gastric and colonic mucosa, it was absent or reduced in most gastric and colorectal tumor samples. Only39.6%of gastric and14.9%of colorectal tumors showed high expression. Low expression of JPH3protein was significantly correlated with poor differentiation, positive lymph nodes metastasis, present of distant metastasis, aggresive tumor invasion, poor tumor stage and poor prognosis in gastric cancer (p<0.05). Restoring JPH3expression inhibited tumor cell growth and migration in vitro, incresed plasmic Ca2+, promoted apoptosis, induced and promoted ER stress. JPH3induced TRB3protein expression and inhibited phospholization and activation of Akt.Conclusions:JPH3acts as a tumor suppressor and its methylation is a frequent, cancer-specific event that may serve as a biomarker for tumor diagnosis and prognosis assessment. Restoring JPH3expression strongly reduced proliferation and migration, and induced both apoptosis may through mitochondria and TRB3-Akt signaling.