LIX1-like protein promotes liver cancer progression via miR-21-3p-mediated inhibition of fructose-1,6-bisphosphatase

• Published in: Acta pharmaceutica Sinica. B Vol. 11; no. 6; pp. 1578 - 1591
• Main Authors: Zou, Jie, Zhu, Xiaoyun, Xiang, Dejuan, Zhang, Yanqiu, Li, Jie, Su, Zhigui, Kong, Lingyi, Zhang, Hao
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.06.2021; Elsevier
• Subjects: FBP1; Gluconeogenesis; Glucose metabolism; Hepatocellular carcinoma; LIX1L; Metastasis; miR-21-3p; Original; Proliferation; LIX1L; Hepatocellular carcinoma; HCC; miR-21-3p; Proliferation; Metastasis; DEN; NASH; EMT; ECAR; Glucose metabolism; shRNA; CCl4; miRNA; FBP1; Seq; Gluconeogenesis
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2021.02.005

Limb and CNS expressed 1 like (LIX1L) is over-expressed in several types of tumors. However, the function of LIX1L in glucose metabolism and hepatocellular carcinoma (HCC) progression remains elusive. Here we report that LIX1L is over-expressed in human HCC tissues, which predicts unfavorable prognosis. LIX1L deficiency in vivo significantly attenuated liver cancer initiation in mice. Functional studies indicated that LIX1L overexpression elevated proliferation, migratory, invasive capacities of HCC cells in vitro, and promoted liver cancer growth and metastasis in vivo. LIX1L knockdown up-regulated fructose-1,6-bisphosphatase (FBP1) expression to reduce glucose consumption as well as lactate production. Mechanistically, LIX1L increased miR-21-3p expression, which targeted and suppressed FBP1, thereby promoting HCC growth and metastasis. MiR-21-3p inhibitor could abrogate LIX1L induced enhancement of cell migration, invasion, and glucose metabolism. Inhibition of miR-21-3p suppressed tumor growth in an orthotopic tumor model. Our results establish LIX1L as a critical driver of hepatocarcinogenesis and HCC progression, with implications for prognosis and treatment. Limb and CNS expressed 1 like (LIX1L) promotes liver cancer progression via miR-21-3p-mediated inhibition of fructose-1,6-bisphosphatase. LIX1L and miR-21-3p may be important cellular targets for designing new therapies against liver cancer. [Display omitted]