TMC7 promotes colorectal cancer metastasis via inhibition of PKN2 and regulation of hypoxia-adaptive responses.

Metastasis is the leading cause of mortality in colorectal cancer (CRC). The hypoxic tumor microenvironment contributes to CRC progression by activating hypoxia-adaptive responses and the Warburg effect. This study investigates the role of transmembrane channel-like protein 7 (TMC7) in CRC metastasis. TMC7 is significantly upregulated in CRC tissues in patients, particularly in metastatic lesions. High TMC7 expression was associated with reduced survival and a higher incidence of metachronous liver metastases. Moreover, TMC7-high tumors exhibited enhanced glucose uptake. In vitro, TMC7 promoted CRC cell proliferation and invasion under hypoxic conditions, accompanied by HIF-1α nuclear translocation and activation of hypoxia-adaptive responses. In vivo, TMC7 significantly accelerated lung metastasis and shortened overall survival in a nude mouse xenograft model. Mechanistically, protein kinase N2 (PKN2) acts as a negative regulator of HIF1α activity, suppressing hypoxia adaptation and glycolysis. TMC7 inhibited PKN2 activity, thereby relieving its repression on HIF1α and facilitating HIF1α nuclear accumulation. This cascade ultimately enhances glycolytic flux and supports metastatic progression. Importantly, ectopic expression of PKN2 reversed the pro-metastatic and metabolic reprogramming phenotypes induced by TMC7. Furthermore, elevated TMC7 predicted inferior outcomes following chemotherapy and immunotherapy. Together, these findings uncover a novel TMC7-PKN2-HIF1α signaling axis that drives CRC metastasis through regulation of hypoxia adaptation and the Warburg effect. This study provides new mechanistic insights into CRC metastasis and highlights TMC7 as a potential therapeutic target for precision treatment of metastatic disease.