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LDH家族的一种特定同工酶，可调节某些恶性肿瘤的侵袭和转移。然而，关于其在肺腺癌（LUAD）进程中的作用知之甚少。因此，我们通过免疫组化研究了LDHC的表达，并分析了其在88个LUAD标本中的临床意义。在体内和体外探索了LDHC在细胞增殖，迁移和侵袭中的作用和分子机制。。结果，我们发现高LDHC表达与侵略性LUAD的临床病理特征和预后不良显着相关。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。我们进一步证明了LDHC的过表达影响细胞增殖相关蛋白（细胞周期蛋白D1和c-Myc）和上皮-间质转化（EMT）相关蛋白（MMP-2，MMP-9，E-钙黏着蛋白，波形蛋白， Twist，Slug和Snail）在体外和体内。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。用PI3K抑制剂治疗可通过抑制细胞增殖，迁移和侵袭来逆转LDHC过表达的效应，同时降低p-Akt和p-GSK3β的水平。在过表达LDHC的A549细胞中，PI3K抑制作用还逆转了细胞增殖相关蛋白和EMT相关蛋白。总之，LDHC通过激活PI3K / Akt /GSK-3β途径促进LUAD细胞的增殖，迁移，侵袭和EMT。