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

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.

STAT3 and Its Pathways Dysregulation – Underestimated Role in Urological Tumors

“…The level of STAT3 was increased in high-grade NMIBC tumors. It was also found useful to distinguish cancer type [38,40]. Elevated pSTAT3 Ser727 level was associated with significantly poorer prognosis, higher cancer recurrence rate and lower cancer-specific survival in UTUC.…”

“…On the other hand, fibroblasts produce CCL3, which prevents PLZF expression. Scientists presented a part of complicated relationship between fibroblasts and PCa cells, describing a potentially useful CCL3/PLZF/SHP1/STAT3 cascade [40]. Zhao et al reported that highly concentrated lactoferrin (LTF) significantly decreases STAT3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels, which result in immune TME changes [41].…”