STAT3 phosphorylation is required for the HepaCAM‐mediated inhibition of castration‐resistant prostate cancer cell viability and metastasis

Abstract

Background Castration‐resistant prostate cancer (CRPC) is an advanced disease that is difficult to treat, the mechanism of it is unclear. This study illustrated the function of hepatocyte cell adhesion molecule (HepaCAM) on CRPC cell viability and metastasis. Methods The expression of HepaCAM and p‐STAT3 in CRPC tissues were determined by immunohistochemistry and western blot analysis. Cell Counting Kit‐8 and colony formation assays were deployed to analyze the growth ability of CRPC cells following the adenovirus‐mediated re‐expression of HepaCAM. CRPC cell migration and invasion capacity were investigated by wound healing and Matrigel‐coated transwell assays, respectively. The messenger RNA or protein levels of p‐STAT3, CyclinD1, cMyc, MMP2, MMP9, and VEGF were determined by reverse transcription (RT) followed by quantitative real‐time polymerase chain reaction (RT‐qPCR), and western blot analysis after either HepaCAM re‐expression alone or in combination with IL‐22 treatment. A CRPC orthotopic xenograft mouse model was applied to investigate the functional effect of HepaCAM on the metastasis of CRPC cells to the lungs. Results The expression levels of HepaCAM were decreased while those of p‐STAT3 were elevated in CRPC cells compare with surrounding benign tissues (p < .001). The overexpression of HepaCAM in CRPC cells notably reduced proliferation, migration, and invasion by inhibiting the expression of p‐STAT3, CyclinD1, cMyc, MMP2, MMP9, and VEGF (p < .05). In addition, the expression of HepaCAM significantly inhibited the IL‐22/p‐STAT3 axis and the metastasis of CRPC cells to the lungs. Conclusions Our data suggested that HepaCAM suppressed the viability of CRPC cells via the IL‐22/p‐STAT3 axis and inhibited the metastasis of CRPC cells from the prostate to the lungs (p < .05).

STAT3 and Its Pathways Dysregulation – Underestimated Role in Urological Tumors

“…IL-6/STAT3/PD-L1 pathway was shown to take part in EMT promotion in bladder cancer [27]. Moreover, reduced STAT3 and PD-L1 levels were linked to inhibited proliferation, invasion and immune escape of RCC cells [29].…”

“…There is also lots of downstream targets being under the control of STAT3. Overexpressed STAT3 forces cyclin D1, Bcl-2, Bcl-xL and survivin expression which have proliferative and antiapoptotic properties [28][29][30]. PCa cells may also avoid apoptosis by inhibited expression of caspase 3 and caspase 9 through STAT3 activity [31,32].…”

“…Results were pictured not only by reduced levels of STAT3 target genes, but also by the absence of any lung metastatic areas in mice. Restoring expression of HepaCAM might be a promising perspective for CRPC patients [29]. Lin et al reported that CYP1B1, an enzyme catalyzing the synthesis of 4-hydroxy-17β-estradiol (4-OHE2) from estradiol, might contribute to the development of CRPC by promoting PCSCs characteristics.…”

Molecular Landscape of LncRNAs in Prostate Cancer: A focus on pathways and therapeutic targets for intervention

“…Upregulation of STAT3 promotes metastasis of prostate tumor to bone [192]. STAT3 signaling activation elevates CRPC cell viability and metastasis [193]. Exposing CRPC cells to enzalutamide (Enz) elevates lncRNA-p21 expression that is required for neuroendocrine differentiation (NED).…”

“…ncRNAs are considered as potent regulators of NF-κB signaling in cancer [227]. The increasing evidence demonstrates that NF-κB signaling activation can significantly promote progression of prostate cancer cells and induces their resistance to therapy [193,228,229]. In this section, we provide a discussion of lncRNAs role in NF-κB regulation in prostate cancer.…”