IGF2BPs-regulated TIN2 confers the malignant biological behaviors of gastric cancer cells.

Background: Telomere maintenance is an important feature of tumor cells. Telomeric-repeat binding factor 1 interaction nuclear protein 2 (TIN2), a key member of the shelterin proteins, functions in regulating telomere structure, length and function. Our work sought to investigate the role of TIN2 in controlling gastric cancer (GC) malignant biological behaviors.

Methods: The mRNA and protein expressions were examined by qRT-PCR, western blot and immunofluorescence assays. The relative telomerase activity and telomere length were detected using the corresponding kit and qRT-PCR, respectively. The proliferation, migration and invasion abilities were detected by CCK8 and transwell assays, respectively. Cellular oxidative stress level and Fe content were assessed by DCFH-DA staining and ELISA assays, respectively. The interaction between IGF2BP1/2/3 and TIN2 was analyzed by RIP and RNA pull down assays.

Results: TIN2 expression was significantly increased in GC cells compared with it in gastric mucosal epithelial cells. TIN2 knockdown could impair telomerase function and induce DNA injury in GC cells. Moreover, silencing of TIN2 greatly repressed cell proliferation, metastasis, and autophagy in GC cells. Likewise, the antioxidant capacity and Fe content were enhanced after TIN2 depletion, leading to the activation of cellular ferroptosis. In terms of mechanism, TIN2 mRNA could be recognized by IGF2BP1/2/3, and its mRNA expression and stability were decreased upon IGF2BP1/2/3 was knocked down.

Conclusion: Knockdown of TIN2 could restrained telomerase function and the malignant abilities of proliferation, metastasis and autophagy but induced ferroptosis of GC cells, which suggested that targeting TIN2 might be a therapeutic strategy for GC.