Researchers found an increase in cancer aggressiveness in cholangiocarcinoma (CCA) cells exposed to lactic acidosis due to the upregulation of ALDH1A3, as published in Life Sciences.

The team derived information on ALDH1A3 expression in CCA cells from the Gene Expression Omnibus datasets. They also used several human CCA cell lines to demonstrate increased ALDH1A3 expression in a lactic acidosis medium using real-time polymerase chain reaction and Western blotting, and how this translated to increased aggressiveness as well as increased medication resistance.

Cancer cells produce large amounts of lactic acid due to increased aerobic glycolysis and glutaminolysis. In addition to demonstrating the increased expression of ALDH1A3, the further analysis noted that the high ALDH1A3 was an independent risk factor for shorter survival seen in patients with CCA.

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Through suppression of ALDH1A3 expression, the team also noted a decrease in cancer “aggression”—decreased cell proliferation, colony formation, migration, and invasion. This further supports the role of ALDH1A3 in promoting the metastatic potential of cancer cells.

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Notably, silencing ALDH1A3 also increased the sensitivity of gemcitabine-resistant cells to gemcitabine, highlighting the role of ALDH1A3 in drug resistance development. The researchers were also able to identify the EGFR/STAT3 axis as the molecular pathway that upregulates ALDH1A3 expression.

This study is of considerable significance as it is the first to report the impact of lactic acidosis on ALDH1A3 expression in CCA cells, with its findings consistent with previous studies done on ALDH1A3 expression in other cancers including gliomas, pancreatic adenocarcinoma, and breast cancer. The study findings highlight ALDH1A3 as a promising target for cancer treatment, possibly improving clinical outcomes in patients with CCA in the future.


Thamrongwaranggoon U, Detarya M, Seubwai W, et al. Lactic acidosis promotes aggressive features of cholangiocarcinoma cells via upregulating ALDH1A3 expression through EGFR axis. Life Sci. Published online May 19, 2022. doi:10.1016/j.lfs.2022.120648