Acidosis, regardless of
hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize. Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of
cancer progression, the unrevealed core mechanisms underlying the direct effect of acidification on
tumorigenesis have hindered the discovery of novel therapeutic targets and clinical
therapy. Here, chemical-induced and transgenic mouse models for colon, liver and
lung cancer were established, respectively. miR-7 and TGF-β2 expressions were examined in clinical tissues (n = 184).
RNA-seq,
miRNA-seq, proteomics, biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced
lung cancer metastasis. Our data show that
lung cancer is sensitive to the increased acidification of TME, and acidic TME-induced
lung cancer metastasis via inhibition of miR-7-5p. TGF-β2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the
lung cancer. Indeed, overexpression of miR-7-5p reduces the acidic pH-enhanced
lung cancer metastasis. Furthermore, the human lung
tumor samples also show a reduced miR-7-5p expression but an elevated level of activated TGF-β2; the expressions of both miR-7-5p and TGF-β2 are correlated with patients' survival. We are the first to identify the role of the miR-7/TGF-β2 axis in acidic pH-enhanced
lung cancer metastasis. Our study not only delineates how acidification directly affects
tumorigenesis, but also suggests miR-7 is a novel reliable
biomarker for acidic TME and a novel therapeutic target for
non-small cell lung cancer (NSCLC) treatment. Our study opens an avenue to explore the pH-sensitive subcellular components as novel therapeutic targets for
cancer treatment.