Department of Clinical Laboratory, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China.
Department of Clinical Laboratory, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China; Department of Laboratory Medicine,Shanghai East Hospital,Tongji University School of Medicine, Shanghai, 200120, China.
Exp Cell Res. 2021 Jan 15;398(2):112414. doi: 10.1016/j.yexcr.2020.112414. Epub 2020 Dec 8.
The cancer/testis antigen lactate dehydrogenase-C4 (LDHC) is a specific isoenzyme of the LDH family that regulates invasion and metastasis in some malignancies; however, little is known regarding its role in progression of lung adenocarcinoma (LUAD). Thus, we investigated LDHC expression by immunohistochemistry, and analyzed its clinical significance in 88 LUAD specimens. The role and molecular mechanisms subserving LDHC in cellular proliferation, migration, and invasion were explored both in vitro and in vivo. As a result, we found that high LDHC expression was significantly correlated with clinicopathological features of aggressive LUAD and a poor prognosis. Overexpression of LDHC induced LUAD cells to produce lactate and ATP, increased their metastatic and invasive potential-, and accelerated xenograft tumor growth. We further demonstrated that overexpression of LDHC affected the expression of cell proliferation-related proteins (cyclin D1 and c-Myc) and epithelial-mesenchymal transition (EMT)-related proteins (MMP-2, MMP-9, E-cadherin, Vimentin, Twist, Slug, and Snail) both in vitro and in vivo. Finally, excessive activation of LDHC enhanced the phosphorylation levels of AKT and GSK-3β, revealing activation of the PI3K/Akt/GSK-3β oncogenic-signaling pathways. Treatment with a PI3K inhibitor reversed the effects of LDHC overexpression by inhibiting cellular proliferation, migration, and invasion, with diminished levels of p-Akt and p-GSK3β. PI3K inhibition also reversed cell proliferation-related and EMT-related proteins in LDHC-overexpressing A549 cells. In conclusion, LDHC promotes proliferation, migration, invasion, and EMT in LUAD cells via activation of the PI3K/Akt/GSK-3β pathway.
癌症/睾丸抗原乳酸脱氢酶-C4（LDHC）是乳酸脱氢酶家族的一种特异性同工酶，它调节某些恶性肿瘤的侵袭和转移；然而，关于其在肺腺癌（LUAD）进展中的作用知之甚少。因此，我们通过免疫组织化学法检测 LDHC 的表达，并分析了 88 例 LUAD 标本中 LDHC 的临床意义。我们在体外和体内研究了 LDHC 在细胞增殖、迁移和侵袭中的作用和分子机制。结果发现，高 LDHC 表达与侵袭性 LUAD 的临床病理特征和不良预后显著相关。LDHC 的过表达诱导 LUAD 细胞产生乳酸和 ATP，增加其转移和侵袭潜能，并加速异种移植肿瘤的生长。我们进一步证明，LDHC 的过表达影响细胞增殖相关蛋白（cyclin D1 和 c-Myc）和上皮-间充质转化（EMT）相关蛋白（MMP-2、MMP-9、E-cadherin、Vimentin、Twist、Slug 和 Snail）的表达，无论是在体外还是体内。最后，LDHC 的过度激活增强了 AKT 和 GSK-3β的磷酸化水平，揭示了 PI3K/Akt/GSK-3β致癌信号通路的激活。PI3K 抑制剂的治疗通过抑制细胞增殖、迁移和侵袭，降低 p-Akt 和 p-GSK3β的水平，逆转了 LDHC 过表达的作用。PI3K 抑制也逆转了 LDHC 过表达的 A549 细胞中与细胞增殖和 EMT 相关的蛋白。总之，LDHC 通过激活 PI3K/Akt/GSK-3β通路促进 LUAD 细胞的增殖、迁移、侵袭和 EMT。
