Jishui ZHANG, Wenhao LV, Yagang LIU, Weihua FU, Baosheng CHEN, Qiutong MA, Xin GAO, Xiuxia CUİ

Knockdown of Serum- and Glucocorticoid-Regulated Kinase 1 Enhances Cisplatin Sensitivity of Gastric Cancer Through Suppressing the Nuclear Factor Kappa-B Signaling Pathway

Background: Previous studies have published the promoting effect of serum and glucocorticoid-regulated kinase 1 (SGK1) in various malignant tumors. However, whether SGK1 promotes gastric cancer remains a mystery. Aims: To clarify the function of SGK1 in gastric cancer and its potential regulatory mechanism. Study Design: Cell culture study. Methods: The SGK1-silenced model was generated in two gastric cancer cell lines and further evaluated their malignant behavior and susceptibility to cisplatin. The interaction between miR-15a-5p and SGK1 was evaluated by the luciferase reporter assay. The knockdown efficiency of SGK1 was confirmed by RT- qPCR and Western blot assays. Cell proliferation rate was assessed with CCK-8 assay, and flow cytometry was used to determine cell cycle progression and apoptosis. Results: Western blot data displayed an elevated level of SGK1 in gastric cancer cell lines. Functionally, SGK1 deficiency suppressed gastric cancer cell proliferation (P < .01) by acting on cell-cycle progression. Moreover, SGK1 deficiency suppressed cell invasion and migration of gastric cancer cells (P < .01). Further, the silencing of SGK1 obviously suppressed cell proliferation and induced apoptosis of the cells after cisplatin treatment (P < .01), indicating that SGK1 deficiency facilitated the chemosensitivity of these 2 gastric cancer cell lines to cisplatin. Mechanically, downregulation of SGK1 repressed the cytoplasm-to-nucleus translocation of NF-κB p65. Interestingly, we found that miR-15a-5p binds to the 3'UTR of SGK1, which was confirmed using luciferase activity assay (P < .05). Moreover, the data suggested that SGK1 reversed the suppression effect of miR-15a-5p on gastric cancer cell migration (P < .01). Conclusion: Loss of SGK1 suppresses the malignant behavior of gastric cancer cells and increases cisplatin sensitivity by restraining the NF-κB signaling pathway. Moreover, SGK1 may exert an inhibitory effect in gastric cancer by being targeted by miR-15a-5p. Therefore, SGK1 may be a prospective target for future gastric cancer therapy.

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