PDZ and LIM domain protein 4 suppresses the growth and invasion of ovarian cancer cells via inactivation of STAT3 signaling
Introduction
Ovarian cancer is one of the most lethal gynecologic malignancies worldwide [1]. The prognosis of advanced ovarian cancer is poor, with a 5-year survival rate of 10–30% [2,3]. Metastasis is a major cause of ovarian cancer-related deaths [4]. Surgery in combination with chemotherapy is the primary treatment for ovarian cancer [5,6]. Understanding the exact mechanism underlying the invasion and metastasis of ovarian cancer is of significance in treating advanced ovarian cancer.
Several signaling pathways in particular the STAT3 pathway have been reported to be involved in the progression of ovarian cancer [7,8]. STAT3 as a member of the STAT family of transcription factors shows the ability to enhance ovarian cancer invasion and metastasis [9]. The STAT3 pathway contributes to the stem cell-like properties of ovarian cancer cells [10,11]. Upon stimulation with cytokines and growth factors, STAT3 can be phosphorylated by receptor-associated Janus kinases (JAK), leading to STAT3 nuclear translocation and transactivation of target genes such as CCND1 and MMP9 [12,13]. Therefore, STAT3 signaling is regarded as a promising therapeutic target for ovarian cancer.
PDZ and LIM domain protein 4 (PDLIM4) is a member of the PDLIM family that is composed of conserved PDZ and LIM domains [14]. PDLIM4 has been documented to participate in actin cytoskeleton remodeling and cell motility [15]. Several lines of evidence have indicated the involvement of PDLIM4 in tumor progression [[16], [17], [18]]. For instance, PDLIM4 overexpression suppresses the growth and clonogenicity of colon cancer cells [16]. PDLIM4 is downregulated in prostate cancer relative to adjacent benign tissues [17], and shows the ability to arrest cell cycle progression in prostate cancer cells [18]. Despite these studies, the expression and role of PDLIM4 in ovarian cancer has not been addressed.
In this study, we examined the expression and prognostic significance of PDLIM4 in ovarian cancer. We also characterized the function of PDLIM4 in ovarian cancer cell growth, invasion, and tumorigenesis. In addition, the signaling pathway(s) involved is determined.
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Tissue specimens
In this study, we collected 92 ovarian cancer and 35 adjacent normal ovarian tissues from the patients with ovarian cancer who underwent surgery at the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China). None of them had received any anti-cancer therapy before surgery. Clinicopathological information was retrieved from patient medical records. The median age of these patients was 58 years (range, 26–84 years). The collection and application of patient specimens were approved
Downregulation of PDLIM4 correlates with poor prognosis in ovarian cancer
Immunohistochemistry was performed to examine the expression of PDLIM4 in 92 ovarian cancer and 35 adjacent normal ovarian tissues. Positive PDLIM4 staining (86%) was readily observed in normal ovarian tissues, while only 30% of ovarian cancer tissues showed positive staining for PDLIM4 (Fig. 1A–D). As shown in Table 1, PDLIM4 expression levels were significantly correlated with advanced tumor stage (P = 0.003) and lymph node metastasis (P < 0.0001). The prognostic impact of PDLIM4 expression
Discussion
Epigenetic silencing of PDLIM4 via hypermethylation is frequently detected in cancers [17,26,27]. For instance, Morris et al. [27] reported that >30% of renal cell carcinoma has promoter hypermethylation on PDLIM4 gene and reduced expression of PDLIM4. Botezatu et al. [26] demonstrated that PDLIM4 promoter methylation is increased in thyroid cancer relative to normal tissues. Feng et al. [28] documented that PDLIM4 promoter is hypermethylated in primary and metastatic breast cancer samples.
Conclusion
In summary, our data indicate that PDLIM4 is downregulated in ovarian cancer and associated with shorter overall survival of patients with ovarian cancer. Enforced expression of PDLIM4 can remarkably inhibit the proliferation, invasion, and tumorigenesis of ovarian cancer cells. Mechanistic investigation reveals that PDLIM4 blocks the phosphorylation activation of STAT3 and inhibits the expression of CCND1 and MMP9, therefore exerting anti-tumor effects on ovarian cancer. These findings suggest
Declaration of competing interest
There is no conflict of interest.
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