Acidic microenvironment modulates ROR1 to promote epithelial-mesenchymal transition and hepatocarcinoma metastasis
The tendency of metastasis in hepatocarcinoma results in a high rate of mortality, making it a hot research topic in cancer studies. Although tumor acidic microenvironment has been proved to promote cancer metastasis, its 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 kinases-like orphan receptor 1 (ROR1) was distinctly upregulated in acid-treated cells. In addition, siRNA knockdown of ROR1 could effectively inhibit acid-induced cell migration, invasion and epithelial-mesenchymal transition (EMT). Importantly, neutralization of acidic environment with NaHCO3 could downregulate acid-stimulated ROR1 expression, thereby retarding cell metastatic potential. Especially, the formation of metastatic nodules was significantly increased after intrapulmonary injection of acid stimulated cancer cells, which were inhibited by pretreating with NaHCO3. In summary, we reveal that tumor acidic microenvironment modulates ROR1 expression to promote tumor metastasis, which provides not only a better understanding of molecular mechanism related to metastasis, but a promising target for tumor management.