Journal of advanced research · 2025
TMEM158 promotes ICC metastasis via inducing lactic acid mediated reduction of actin skeleton stiffness of ICC cells.
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Chen Peng, Yang Jing, Jin Shengxi, Li Yujie, Li Duguang, Zhong Cheng, Zhang Yiyin, Xia Qiming, Fan Xiaoxiao, Lin Hui
Аннотация
INTRODUCTION: The survival rate of patients with intrahepatic cholangiocarcinoma (ICC) is extremely low mainly because of its high metastatic characteristic, pushing us to explore effective targets inhibiting the metastasis of ICC.
OBJECTIVES: To explore potential therapeutical targets to restrict the metastasis of ICC.
METHODS: The potential targets were screened via RNA sequencing and verified in cells and tissues. The prognostic value of TMEM158 was explored in ICC patients. The abilities of TMEM158 on affecting the metastasis of ICC were detected in cells and mice models. The cell actin skeleton stiffness was measured by phalloidin staining. The effect of TMEM158 on lactic acid (LA) generation was explored via metabolic flow and relative mechanism was detected by co-immunoprecipitation and immunofluorescence. The relationship between HIF-1A and TMEM158 was explored by dual luciferase reporter gene experiment.
RESULTS: TMEM158 was identified as a potential candidate over-expressed in ICC, especially with metastasis, that is linked to reduced overall survival. Besides, functional studies indicated that TMEM158 silencing inhibits ICC metastasis in vivo and in vitro through decreasing cell actin skeleton stiffness of ICC cells, and visa versa. Moreover, mechanically, lactic acid (LA) is validated as the bridge connecting TMEM158 and skeleton stiffness and TMEM158 induces the generation of LA via interaction with and activating Ras protein and subsequently enhancing glucose transporter 3 (Glut3) mediated glycolysis in ICC cells. Finally, HIF-1A directly targets the promoter region of TMEM158 and thus increases its level in ICC.
CONCLUSION: TMEM158 reduced the actin skeleton stiffness of ICC cells through activating Ras protein mediated generation of LA, which finally results in enhanced metastasis of ICC. Our work provides a preclinical evidence of concept for TMEM158 as a novel candidate inhibiting the metastasis of ICC.
OBJECTIVES: To explore potential therapeutical targets to restrict the metastasis of ICC.
METHODS: The potential targets were screened via RNA sequencing and verified in cells and tissues. The prognostic value of TMEM158 was explored in ICC patients. The abilities of TMEM158 on affecting the metastasis of ICC were detected in cells and mice models. The cell actin skeleton stiffness was measured by phalloidin staining. The effect of TMEM158 on lactic acid (LA) generation was explored via metabolic flow and relative mechanism was detected by co-immunoprecipitation and immunofluorescence. The relationship between HIF-1A and TMEM158 was explored by dual luciferase reporter gene experiment.
RESULTS: TMEM158 was identified as a potential candidate over-expressed in ICC, especially with metastasis, that is linked to reduced overall survival. Besides, functional studies indicated that TMEM158 silencing inhibits ICC metastasis in vivo and in vitro through decreasing cell actin skeleton stiffness of ICC cells, and visa versa. Moreover, mechanically, lactic acid (LA) is validated as the bridge connecting TMEM158 and skeleton stiffness and TMEM158 induces the generation of LA via interaction with and activating Ras protein and subsequently enhancing glucose transporter 3 (Glut3) mediated glycolysis in ICC cells. Finally, HIF-1A directly targets the promoter region of TMEM158 and thus increases its level in ICC.
CONCLUSION: TMEM158 reduced the actin skeleton stiffness of ICC cells through activating Ras protein mediated generation of LA, which finally results in enhanced metastasis of ICC. Our work provides a preclinical evidence of concept for TMEM158 as a novel candidate inhibiting the metastasis of ICC.