SASH1 suppresses triple-negative breast cancer cell invasion through YAP-ARHGAP42-actin axis
ONCOGENE
Authors: Jiang, Ke; Liu, Peng; Xu, Huizhe; Liang, Dapeng; Fang, Kun; Du, Sha; Cheng, Wei; Ye, Leiguang; Liu, Tong; Zhang, Xiaohong; Gong, Peng; Shao, Shujuan; Wang, Yifei; Meng, Songshu
Abstract
Triple-negative breast cancer (TNBC) is extremely aggressive and lacks effective therapy. SAM and SH3 domain containing1 (SASH1) has been implicated in TNBC as a candidate tumor suppressor; however, the mechanisms of action of SASH1 in TNBC remain underexplored. Here, we show that SASH1 was significantly downregulated in TNBC patients samples compared with other subtypes of breast cancer. Ectopic SASH1 expression inhibited, while depletion of SASH1 enhanced, the invasive phenotype of TNBC cells, accompanied by deregulated expression of MMP2 and MMP9. The functional effects of SASH1 depletion were confirmed in the chicken chorioallantoic membrane and mouse xenograft models. Mechanistically, SASH1 knockdown downregulated the phosphorylation levels of the Hippo kinase LATS1 and its effector YAP (Yes associated protein), thereby upregulating YAP accumulation together with its downstream target CYR61. Consistently, forced SASH1 expression exhibited opposite effects. Pharmacological inhibition of YAP or knockdown of YAP reversed the enhanced cell invasion of TNBC cells following SASH1 depletion. Furthermore, SASH1-induced YAP signaling was LATS1-dependent, which in reverse enhanced phosphorylation of SASH1. The SASH1 S407A mutant (phosphorylation deficient) failed to rescue the altered YAP signaling by SASH1 knockdown. Notably, SASH1 depletion upregulated ARHGAP42 levels via YAP-TEAD and the YAP-ARHGAP42-actin axis contributed to SASH1-regulated TNBC cell invasion. Therefore, our findings uncover a new mechanism for the tumor-suppressive activity of SASH1 in TNBC, which may serve as a novel target for therapeutic intervention.
Upregulation of Tubulointerstitial nephritis antigen like 1 promotes gastric cancer growth and metastasis by regulating multiple matrix metallopeptidase expression
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
Authors: Shan, Zhi-Guo; Sun, Zhen-Wei; Zhao, Li-Qun; Gou, Qiang; Chen, Zhi-Fu; Zhang, Jin-Yu; Chen, Weisan; Su, Chong-Yu; You, Nan; Zhuang, Yuan; Zhao, Yong-Liang
Abstract
Background and Aim Tubulointerstitial nephritis antigen-like 1 (TINAGL1), as a novel matricellular protein, has been demonstrated to participate in cancer progression, whereas the potential function of TINAGL1 in gastric cancer (GC) remains unknown. Methods The expression pattern of TINAGL1 in GC was examined by immunohistochemistry, ELISA, real-time polymerase chain reaction, and Western blot. Correlation between TINAGL1 and matrix metalloproteinases (MMPs) was analyzed by the GEPIA website and Kaplan-Meier plots database. The lentivirus-based TINAGL1 knockdown, CCK-8, and transwell assays were used to test the function of TINAGL1in vitro. The role of TINAGL1 was confirmed by subcutaneous xenograft, abdominal dissemination, and lung metastasis model. Microarray experiments, ELISA, real-time polymerase chain reaction, and Western blot were used to identify molecular mechanism. Results TINAGL1 was increased in GC tumor tissues and associated with poor patient survival. Moreover, TINAGL1 significantly promoted GC cell proliferation and migrationin vitroas well as facilitated GC tumor growth and metastasisin vivo. TINAGL1 expression in GC cells was accompanied with increasing MMPs including MMP2, MMP9, MMP11, MMP14, and MMP16. GEPIA database revealed that these MMPs were correlated with TINAGL1 in GC tumors and that the most highly expressed MMP was MMP2. Mechanically, TINAGL1 regulated MMP2 through the JNK signaling pathway activation. Conclusions Our data highlight that TINAGL1 promotes GC growth and metastasis and regulates MMP2 expression, indicating that TINAGL1 may serve as a therapeutic target for GC.
COA
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