High expression of leucine-rich repeat-containing 8A is indicative of a worse outcome of colon cancer patients by enhancing cancer cell growth and metastasis

Abstract

To survive, cells need to avoid excessive volume change that jeopardizes structural integrity and stability of the intracellular milieu. Searching for the molecular identity of volume-regulated anion channel (VRAC) has yielded multiple potential candidates, but none has been confirmed. Recently, it is reported that leucine-rich repeat-containing 8A (LRRC8A) is a main molecular determinant of VRAC current. The biological functions of LRRC8 family proteins are poorly understood, particularly in cancer. In the present study, we investigated LRRC8A in the most common cancers of the digestive system. LRRC8A proteins were found to be abundantly expressed in the esophagus, stomach, duodenum, colon, rectum, liver and pancreas. LRRC8A was elevated in 60% of colorectal cancer patient tissues, which was higher than that in patients with cancer of the esophagus, stomach, duodenum, liver and pancreas. Colon cancer patients with high- expressed LRRC8A had a survival time of 54.9±5.5 months, shorter than that of patients with low-expressed LRRC8A (77.1±3.7). Moreover, survival time (52.6±7.3 months) of patients with metastases in the lymph nodes was shorter than that of patients without positive lymph nodes (72.2±3.6); patients with positive lymph nodes and an elevated LRRC8A expression had the highest mortality rate (~80%). These rates were not observed in rectal cancer. After LRRC8A protein was knocked down in colon cancer HCT116 cells, VRAC currents, migration and tumorigenesis in nude mice were significantly inhibited. In conclusion, we propose that LRRC8A could be a novel prognostic biomarker for colon cancer patient survival, and that the elevated expression of LRRC8A may enhance cancer cell growth and metastasis, and worsen the outcome of patients.