PDZ and LIM domain protein 4 suppresses the growth and invasion of ovarian cancer cells via inactivation of STAT3 signaling
PDZ and LIM domain protein 4 suppresses the growth and invasion of ovarian cancer cells via inactivation of STAT3 signaling
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DOI：
10.1016/j.lfs.2019.116715
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发表时间：
2019-09-15
期刊：
影响因子：
6.1
通讯作者：
Li, Xueru
中科院分区：
文献类型：
--
作者：
Jia, Yanyan;Shi, Huirong;Li, Xueru
PDZ和LIM结构域蛋白4（PDLIM4）在癌组织中经常被抑制。然而，PDLIM 4在卵巢癌中的表达及其作用尚未得到阐明。主要方法：本研究旨在探讨PDLIM 4在卵巢癌中的表达及其与预后的关系。PDLIM4在卵巢癌细胞生长、侵袭和肿瘤发生中的功能进一步被探索。关键发现：与邻近正常卵巢组织相比，PDLIM4在卵巢癌中下调。PDLIM 4的下调与晚期肿瘤分期和淋巴结转移相关。PDLIM4低表达与卵巢癌患者的总生存期较短显著相关（P = 0.0136）。在生物学上，与空载体转染的细胞相比，PDLIM4过表达抑制CAOV3和SKOV3卵巢癌细胞的增殖、集落形成、迁移和侵袭。一致地，体内数据显示PDLIM4过表达抑制SKOV3异种移植肿瘤的生长。机制研究表明，PDLIM4的过表达阻断了STAT3的磷酸化并抑制了STAT3依赖的转录激活。此外，PDLIM4的异位表达下调卵巢癌细胞中CCND1和MMP 9的表达。拯救实验表明，组成型活性STAT3的过表达逆转PDLIM4诱导的对卵巢癌cells.Significance的抗癌作用：总体而言，PDLIM4下调与卵巢癌患者的侵袭性肿瘤特征和不良预后相关。PDLIM4通过抑制STAT3信号传导抑制卵巢癌细胞的生长和侵袭。本研究为卵巢癌的治疗提供了一个潜在的靶点。
Aims: PDZ and LIM domain protein 4 (PDLIM4) is frequently repressed in cancer tissues. However, the expression and role of PDLIM4 in ovarian cancer has not been addressed.Main methods: In this study, we examined the expression and prognostic significance of PDLIM4 in ovarian cancer. The function of PDLIM4 in ovarian cancer cell growth, invasion, and tumorigenesis was further explored.Key findings: PDLIM4 is downregulated in ovarian cancer compared to adjacent normal ovarian tissues. Downregulation of PDLIM4 is correlated with advanced tumor stage and lymph node metastasis. Low PDLIM4 expression is significantly associated with shorter overall survival in patients with ovarian cancer (P = 0.0136). Biologically, PDLIM4 overexpression suppresses the proliferation, colony formation, migration, and invasion of both CAOV3 and SKOV3 ovarian cancer cells, compared to empty vector-transfected cells. Consistently, in vivo data show that PDLIM4 overexpression inhibits the growth of SKOV3 xenograft tumors. Mechanistic investigation reveals that overexpression of PDLIM4 blocks the phosphorylation of STAT3 and represses STAT3-dependent transcriptional activation. Moreover, ectopic expression of PDLIM4 downregulates the expression of CCND1 and MMP9 in ovarian cancer cells. Rescue experiments demonstrate that overexpression of constitutively active STAT3 reverses PDLIM4-induced anticancer effects on ovarian cancer cells.Significance: Overall, PDLIM4 downregulation is associated with aggressive tumor features and poor prognosis in ovarian cancer patients. PDLIM4 suppresses ovarian cancer cell growth and invasion by inhibiting STAT3 signaling. This study provides a potential therapeutic target for ovarian cancer.