Loss of PDK4 expression promotes proliferation, tumorigenicity, motility and invasion of hepatocellular carcinoma cells
Loss of PDK4 expression promotes proliferation, tumorigenicity, motility and invasion of hepatocellular carcinoma cells
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PDK4表达缺失促进肝细胞癌细胞的增殖、致瘤性、运动性和侵袭性
DOI：
10.7150/jca.43459
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发表时间：
2020-01-01
影响因子：
3.9
通讯作者：
Sun, Yan
中科院分区：
文献类型：
--
作者：
Qin, Yu-Juan;Lin, Tao-Yan;Sun, Yan
尽管丙酮酸脱氢酶激酶（PDK）家族其他成员（即PDK1、PDK2和PDK3）在肿瘤进展中的作用及潜在机制已得到广泛研究且为人熟知，但丙酮酸脱氢酶激酶4（PDK4）在包括肝细胞癌（HCC）在内的多种癌症发生发展中的功能及潜在分子机制在很大程度上仍不明确。在本研究中，我们检测了PDK4在HCC临床组织标本中的表达谱，以及PDK4在HCC细胞增殖、致瘤性、运动性和侵袭性方面的作用。免疫组织化学（IHC）和实时荧光定量聚合酶链反应（qRT-PCR）结果显示，在HCC临床标本队列中，PDK4表达显著下调。此外，基于免疫荧光（ICC）检测发现，HCC细胞的细胞核和细胞质中均存在PDK4蛋白；基于IHC检测发现，HCC临床标本中癌细胞的细胞核和细胞质中也存在PDK4蛋白。CCK-8检测和细胞集落形成实验表明，通过慢病毒介导的RNA干扰（RNAi）稳定敲低内源性PDK4，在体外可显著促进HCC细胞系（即BEL - 7402和BEL - 7404细胞）的增殖，而PDK4沉默在体内可显著增强BEL - 7404细胞的致瘤能力。除了PDK4沉默诱导的增殖和致瘤作用增强外，进一步研究表明，敲低PDK4可导致BEL - 7402和BEL - 7404细胞在体外的迁移和侵袭能力增强。综上所述，这些研究结果表明，PDK4表达缺失有助于HCC的恶性进展。
Although the roles and underlying mechanisms of other PDK family members (i.e., PDK1, PDK2 and PDK3) in tumor progression have been extensively investigated and are well understood, the functions and underlying molecular mechanisms of pyruvate dehydrogenase kinase 4 (PDK4) in the tumorigenesis and progression of various cancers [including hepatocellular carcinoma (HCC)] remain largely unknown. In this study, we examined the expression profile of PDK4 in HCC clinical tissue specimens and the roles of PDK4 in the proliferation, tumorigenicity, motility and invasion of HCC cells. The immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR) results revealed that PDK4 was significantly downregulated in the cohort of HCC clinical specimens. Additionally, PDK4 protein was found in both the nucleus and cytoplasm of HCC cells based on an immunofluorescence (ICC) assay, and PDK4 protein was also found in the nucleus and cytoplasm of cancer cells contained in HCC clinical specimens based on IHC. The CCK-8 assay and cell colony formation assay demonstrated that stable depletion of endogenous PDK4 by lentivirus-mediated RNA interference (RNAi) markedly promoted the proliferation of HCC cell lines (i.e., BEL-7402 and BEL-7404 cells) in vitro, while PDK4 silencing significantly enhanced the tumorigenic ability of BEL-7404 cells in vivo. In addition to enhance proliferation and tumorigenesis induced by PDK4 silencing, additional studies demonstrated that knockdown of PDK4 led to increase migration and invasion of BEL-7402 and BEL-7404 cells in vitro. Taken together, these findings suggest that the loss of PDK4 expression contributes to HCC malignant progression.