Wang Jinghao, Qian Yu, Gao Meiyan
Department of Gynecology and Obstetrics, The Second Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
Cancer Manag Res. 2018 Dec 24;11:251-262. doi: 10.2147/CMAR.S185015. eCollection 2019.
Ovarian cancer is a major type of gynecological malignancy which characterized by the chemoresistance, heterogeneity and highly metastasis. However, the mechanism underlying the progression of ovarian cancer remains elusive. Pyruvate dehydrogenase kinase family plays critical roles in tumorigenesis, and PDK4 has been demonstrated to be an oncogene in many types of cancers. The aim of this study was to identify the role of PDK4 in ovarian cancer.
We explored the PDK4 expression according to the public database containing patients with different effect of chemotherapy. Cell proliferation and invasion assays were used to determine the function of PDK4. Mice xenograft experiment was conducted to test the pro-tumorigenesis function of PDK4 in vivo. Cell apoptosis under treatment of chemo drugs was detected by flow cytometry and TUNEL analysis. Spheroid formation assay and CD133+ cell population were used to determine the PDK4-induced stem-like traits. Immunohistochemical staining was performed to test the expression of PDK4 in ovarian cancer tissues, and Kaplan- Meier curve with log-rank test was performed to determine the association between PDK4 expression and ovarian cancer patients' prognosis.
Overexpression of PDK4 markedly promoted cell proliferation, invasion and tumor growth in vivo. Furthermore, PDK4 confers cell resistant to chemotherapy-induced apoptosis. Mechanically, we demonstrated that PDK4 induced stem-like traits. Meanwhile, PDK4 expression was significantly evaluated in ovarian cancer tissues compared to that in adjacent non-cancer tissues, and high expression of PDK4 was associated with poor overall survival and progression-free survival of ovarian cancer patients.
These results identify a novel role of PDK4 in regulating cell stem-like trait, which directly enhances the cell proliferation, invasion and chemoresistance in ovarian cancer, and targeting PDK4 could be a potential approach for ovarian cancer treatments.
卵巢癌是妇科恶性肿瘤的主要类型，具有化疗耐药性、异质性和高转移性。然而，卵巢癌进展的潜在机制仍不清楚。丙酮酸脱氢酶激酶家族在肿瘤发生中起关键作用，并且已证明PDK4在多种癌症中是一种癌基因。本研究的目的是确定PDK4在卵巢癌中的作用。
我们根据包含不同化疗效果患者的公共数据库探索PDK4表达。使用细胞增殖和侵袭试验来确定PDK4的功能。进行小鼠异种移植实验以在体内测试PDK4的促肿瘤发生功能。通过流式细胞术和TUNEL分析检测化疗药物处理下的细胞凋亡。使用球体形成试验和CD133+细胞群体来确定PDK4诱导的干细胞样特征。进行免疫组织化学染色以检测卵巢癌组织中PDK4的表达，并进行Kaplan-Meier曲线和对数秩检验以确定PDK4表达与卵巢癌患者预后之间的关联。
PDK4的过表达显著促进体内细胞增殖、侵袭和肿瘤生长。此外，PDK4赋予细胞对化疗诱导的凋亡的抗性。在机制上，我们证明PDK4诱导干细胞样特征。同时，与相邻非癌组织相比，卵巢癌组织中PDK4表达显著上调，并且PDK4的高表达与卵巢癌患者的总生存期和无进展生存期差相关。
这些结果确定了PDK4在调节细胞干细胞样特征中的新作用，其直接增强卵巢癌细胞的增殖、侵袭和化疗耐药性，靶向PDK4可能是卵巢癌治疗的一种潜在方法。
