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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- β 2 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- β 2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF- β 2 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- β 2; the expressions of both miR-7-5p and TGF- β 2 are correlated with patients' survival. We are the first to identify the role of the miR-7/TGF- β 2 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. Extracellular acidosis, hallmark of tumor microenvironment, remarkably suppressed miR-7-5p generation to directly active TGF- β 2 expression, which specifically sustained metastasis in lung cancer cells while protect normal cells from death. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract The annual sea surface temperature increased at a rate of 0.038 to 0.074 °C/year in recent decade, and pH decreased at a rate of 0.012–0.014/year in two coastal waters of the South China Sea. Therefore, a culture experiment was conducted to study the effects of acidification and warming on coral calcification rates. The calcification of three coral species were significantly reduced during the exposure to elevated CO 2 , while other three coral species were not significantly affected. The reef coral Pocillopora damicornis was resistant to high CO 2 , but was not able to survive during the exposure to 33 °C in our culture experiments. Our findings suggested that some corals might not survive in tropical areas if coral could not adapt to warming rapidly, and subtropical coastal waters with temperature of <30 °C will serve as refugia for the corals resistant to high CO 2 at the end of this century. Highlights • SST increased at rates of 0.038–0.074 °C/year in recent decade in the SCS. • pH decreased faster than previous prediction in our study sites. • Some reef corals were not able to survive at 33 °C in our culture experiments. • Subtropical waters with temperature of <30 °C may serve as refugia for corals. [ABSTRACT FROM AUTHOR]