Lactic acidosis promotes aggressive features of cholangiocarcinoma cells via upregulating ALDH1A3 expression through EGFR axis

Lactic acidosis (LA) generated in tumor microenvironment promotes tumor metastasis and drug resistance. This study aimed to demonstrate the impacts and the mechanisms of LA on aldehyde dehydrogenase1A3 (ALDH1A3) in promoting aggressiveness and gemcitabine resistance in cholangiocarcinoma (CCA) cell lines. The clinical relevance and the molecular pathway related to the upregulation of ALDH1A3 in LA cells will be revealed.

ALDH1A3 expression and its clinical significances in CCA tissues were analyzed using the GEO databases. Human CCA cell lines, KKU-213A-LA and KKU-213B-LA maintained in the LA medium were studied and compared with its parental cells cultured in normal medium. Aggressive features-proliferation, colony formation, migration, invasion, and gemcitabine response were determined. Expression of ALDH1A3, EGFR and the downstream effectors were analyzed using real-time PCR and Western blotting.

ALDH1A3 was upregulated in patient CCA tissues and correlated with LDHA and shorter survival of CCA patients. mRNA and protein of ALDH1A3 were increased in LA cells. Attenuation of ALDH1A3 expression by siRNA significantly reduced cell proliferation, colony formation, migration, invasion, and gemcitabine resistance of LA cells, and gemcitabine resistant cells. The EGF/EGFR signaling via Erk and STAT3 was pinned to be involved in the induction of ALDH1A3 expression in LA cells. The transcriptomic analysis from TCGA dataset supported the links between LDHA, EGFR and ALDH1A3 in several tumor tissues.

Lactic acidosis upregulated EGFR and ALDH1A3 expression, leading to the aggressiveness of CCA cells. The EGFR/ALDH1A3 axis could be a novel therapeutic target to eradicate metastatic CCA.