Antagonism between HTRA3 and TGFβ1 Contributes to Metastasis in Non–Small Cell Lung Cancer

High temperature requirement A3 (HTRA3, long and short isoforms) is a member of the HtrA family and has been implicated as a tumor suppressor in cancer progression in multiple cancer types, yet its molecular functions in non-small cell lung cancer (NSCLC) are not well understood. Here, we report that decreased levels of HTRA3 negatively correlate with elevated TGFβ1 in lung tumor tissue with metastasis. Furthermore, high expression of HTRA3 indicated better prognosis independent of TGFβ1 expression. In NSCLC cell lines, exogenous TGFβ1 significantly downregulated the level of HTRA3, especially the long isoform, during induction of epithelial-mesenchymal transition (EMT). Mechanistically, c-Jun, which is elevated by TGFβ1, directly bound the promoter of HTRA3-L and inhibited its transcription. As a negative feedback loop, overexpression of HTRA3-L attenuated TGFβ1-mediated invasion-metastasis cascades via activation of SMAD2/3 and sensitized cells to anti-PD-L1 treatment. Taken together, our findings suggest that in the early stages of cancer, overexpressed HTRA3 acts as a brake on the oncogenic effects of TGFβ1 and inhibits tumor metastasis. In later stages, the role of HTRA3 is weakened and TGFβ1 efficiently promotes EMT in the absence of the HTRA3 brake. SIGNIFICANCE: This study provides new mechanistic insight of the interaction between HTRA3 and TGFβ in lung cancer by illustrating that HTRA3 is a novel mediator acting as a suppressor of TGFβ1-related oncogenic effects.