Elsevier

Life Sciences

Volume 233, 15 September 2019, 116715
Life Sciences

PDZ and LIM domain protein 4 suppresses the growth and invasion of ovarian cancer cells via inactivation of STAT3 signaling

https://doi.org/10.1016/j.lfs.2019.116715Get rights and content

Abstract

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.

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.

Section snippets

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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