Crosstalk Between Prostate Cancer Cells and Tumor-Associated Fibroblasts Enhances the Malignancy by Inhibiting the Tumor Suppressor PLZF.

Kum Hee Noh,Eunhee Yi,Haeri Lee,Song-Hee Lee,Pahn-Shick Chang,Ae Jin Jeong,Sang-Kyu Ye,Cheol Kwak

doi:10.3390/cancers12051083

Abstract

Although prostate cancer is clinically manageable during the early stages of progression, metastatic progression severely compromises the prognosis and leads to mortality. Constitutive activation of STAT3 has been connected to prostate cancer malignancy, and abolishing the STAT3 activity may diminish tumor growth and metastasis. However, its suppressor genes and pathways have not been well established. In this study, we show that promyelocytic leukemia zinc finger (PLZF) has a putative tumor-suppressor function in prostate cancer by inhibiting phosphorylation of STAT3. Compared with a benign prostate, high-grade prostate cancer patient tissue was negatively correlated with PLZF expression. PLZF depletion accelerated proliferation and survival, migration, and invasion in human prostate cancer cells. Mechanistically, we demonstrated a novel role of PLZF as the transcriptional regulator of the tyrosine phosphatase SHP-1 that inhibits the oncogenic JAKs–STAT3 pathway. These results suggest that the collapse of PLZF expression by the CCL3 derived from fibroblasts accelerates the cell migration and invasion properties of prostate cancer cells. Our results suggest that increasing PLZF could be an attractive strategy for suppressing prostate cancer metastasis as well as for tumor growth.

Highlights

Prostate cancer is the most frequently diagnosed malignancies and the sixth leading cause of cancer-related death in men worldwide [1]
We found that tumor-induced impetus stimulated fibroblasts to produce CCL3, which promoted prostate cancer growth and metastasis through the reduction of promyelocytic leukemia zinc finger (PLZF)/tyrosine phosphatase SHP-1
We first evaluated the protein levels of PLZF and Tyr705 phosphorylation STAT3 in 40 prostate cancer patients and 10 benign patient tissues, which were categorized according to Gleason scores (GS)

Summary

Introduction

Prostate cancer is the most frequently diagnosed malignancies and the sixth leading cause of cancer-related death in men worldwide [1]. Much research has been done to determine the cause of prostate cancer metastasis, our understanding is still incomplete. For this reason, a better understanding of prostate cancer metastasis would lead to new approaches and targets for preventing or treating metastasis [5]. Tumors can be considered as complex organs composed of tumor cells and various non-malignant stromal cells that form the tumor microenvironment (TME) These stromal cells include endothelial cells, pericytes, immune inflammatory cells, and fibroblasts, all of which are genetically stable and typically not malignant [6,7,8]. Normal fibroblasts can be trained by carcinoma cells to become tumor-associated fibroblasts [13,14,15]

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