Tumor microenvironment acidity modulates ROR1 to promote epithelial–mesenchymal transition and hepatocarcinoma metastasis

Abstract

ABSTRACT The tendency of hepatocarcinoma to metastasize results in a high rate of mortality, making it a hot research topic in cancer studies. Although an acidic tumor microenvironment has been proven to promote cancer metastasis, the underlying regulatory mechanisms remain poorly defined. Here, we found that acidic conditions significantly enhanced cell migration and invasion ability in hepatocellular carcinoma, and the expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) was distinctly upregulated in acid-treated cells. In addition, siRNA-mediated knockdown of ROR1 could effectively inhibit acid-induced cell migration, invasion and epithelial–mesenchymal transition (EMT). Importantly, neutralization of acidic environments with NaHCO3 could downregulate acid-stimulated ROR1 expression, thereby retarding cell metastatic potential. Notably, the formation of metastatic nodules was significantly increased after intrapulmonary injection of acid-stimulated cancer cells, and this was inhibited by pretreating with NaHCO3. In summary, we reveal that an acidic tumor microenvironment modulates ROR1 expression to promote tumor metastasis, providing not only a better understanding of molecular mechanisms related to metastasis, but also a promising target for tumor management.