HK2 and LDHA upregulation mediate hexavalent chromium-induced carcinogenesis, cancer development and prognosis through miR-218 inhibition

• Published in: Ecotoxicology and environmental safety Vol. 279; p. 116500
• Main Authors: Wang, Lin, Zhang, Rui-Ke, Sang, Peng, Xie, Yun-Xia, Zhang, Ye, Zhou, Zhi-Hao, Wang, Kun-Kun, Zhou, Feng-Mei, Ji, Xiang-Bo, Liu, Wen-Jing, Qiu, Jian-Ge, Jiang, Bing-Hua
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.07.2024; Elsevier
• Subjects: Animals; Carcinogenesis - chemically induced; Cell Proliferation - drug effects; Chromium - toxicity; Cr(VI); Hexokinase - genetics; Hexokinase - metabolism; HK2; Humans; Isoenzymes; L-Lactate Dehydrogenase - metabolism; LDHA; Lung Neoplasms - chemically induced; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mice; MicroRNAs - genetics; MiR-218; Occupational Exposure - adverse effects; Prognosis; Tumor growth; Up-Regulation; LDHA; Cr(VI); Tumor growth; HK2; MiR-218
• ISSN: 0147-6513; 1090-2414; 1090-2414
• DOI: 10.1016/j.ecoenv.2024.116500

Hexavalent chromium [Cr(VI)] is one of the most common environmental contaminants due to its tremendous industrial applications, but its effects and mechanism remain to be investigated. Our previous studies showed that Cr(VI) exposure caused malignant transformation and tumorigenesis. This study showed that glycolytic proteins HK2 and LDHA levels were statistically significant changed in blood samples of Cr(VI)-exposed workers and in Cr-T cells compared to the control subjects and parental cells. HK2 and LDHA knockdown inhibited cell proliferation and angiogenesis, and higher HK2 and LDHA expression levels are associated with advanced stages and poor prognosis of lung cancer. We found that miR-218 levels were significantly decreased and miR-218 directly targeted HK2 and LDHA for inhibiting their expression. Overexpression of miR-218 inhibited glucose consumption and lactate production in Cr-T cells. Further study found that miR-218 inhibited tumor growth and angiogenesis by decreasing HK2 and LDHA expression in vivo. MiR-218 levels were negatively correlated with HK2 and LDHA expression levels and cancer development in human lung and other cancers. These results demonstrated that miR-218/HK2/LDHA pathway is vital for regulating Cr(VI)-induced carcinogenesis and human cancer development. [Display omitted] •Long-term exposure of Cr(VI) increased expression levels of glycolysis regulatory enzymes HK2 and LDHA in human blood samples and Cr(VI)-transformed cells.•Silencing HK2 and LDHA inhibited cell proliferation and tube formation.•HK2 and LDHA were direct targets of miR-218. Overexpression of HK2 and LDHA reversed the inhibitory effects of miR-218.•Chronic Cr(VI) exposure induced angiogenesis and carcinogenesis by regulating miR-218/HK2/LDHA signaling.