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Abstract：
Previous study showed that higher expression of prolactin (PRL) was found in CRPC samples compared with hormone-naive prostate cancer (HNPC) and benign prostatic hyperplasia (BPH) samples. We further investigate the function of PRL in prostate cancer (PCa) and explored its downstream effects. We found heterogeneous expression of the PRLR in clinical prostate samples. The VCaP and 22Rv1 cells exhibited PRLR expression. Among the downstream proteins, STAT5B was the dominant subtype in clinical samples and cell lines. Human recombinant PRL stimulation of PCa cells with PRLR expression resulted in increased phosphorylation of STAT5B(pSTAT5B) and progression of PCa in vitro and in vivo, and STAT5B knockdown can suppress the malignant behavior of PCa. To understand the mechanism further, we performed Bioinformatic analysis, ChIP qPCR, and luciferase reporter gene assay. The results revealed that ARRB2 was the transcription target gene of STAT5B, and higher expression of ARRB2 was related to higher aggression and poorer prognosis of PCa. Additionally, Gene set enrichment analysis indicated that higher expression of ARRB2 was significantly enriched in the MAPK signaling pathway. Immunohistochemistry (IHC) demonstrated elevated pSTAT5B, ARRB2, and pERK1/2 expression levels in CRPC tissues compared to HNPC and BPH. Mechanically, ARRB2 enhanced the activation of the MAPK pathway by binding to ERK1/2, thereby promoting the phosphorylation of ERK1/2 (pERK1/2). In conclusion, our study demonstrated that PRL stimulation can promote the progression of PCa through STAT5B/ARRB2 pathway and activation of MAPK signaling, which can be suppressed by intervention targeting STAT5B. Blockade of the STAT5B can be a potential therapeutic target for PCa.
摘要：
先前的研究表明，与未经激素治疗的前列腺癌（HNPC）和良性前列腺增生（BPH）样品相比，CRPC样品中催乳素（PRL）的表达更高。我们进一步研究了PRL在前列腺癌（PCa）中的功能，并探讨了其下游作用。我们发现PRLR在临床前列腺样本中的异质表达。VCaP和22Rv1细胞表现出PRLR表达。在下游蛋白质中，STAT5B是临床样品和细胞系中的主要亚型。具有PRLR表达的PCa细胞的人重组PRL刺激导致STAT5B(pSTAT5B)的磷酸化增加和PCa在体外和体内的进展,STAT5B敲低可以抑制PCa的恶性行为。为了进一步理解该机制，我们进行了生物信息学分析，ChIPqPCR，和荧光素酶报告基因测定。结果表明ARRB2是STAT5B的转录靶基因,ARRB2的高表达与PCa的侵袭性和预后较差有关。此外,基因集富集分析表明，ARRB2的高表达在MAPK信号通路中显著富集。免疫组织化学（IHC）显示pSTAT5B升高，与HNPC和BPH相比，CRPC组织中ARRB2和pERK1/2的表达水平。机械上,ARRB2通过与ERK1/2结合来增强MAPK途径的激活,从而促进ERK1/2(pERK1/2)的磷酸化。总之,我们的研究表明，PRL刺激可以通过STAT5B/ARRB2通路和激活MAPK信号通路促进PCa的进展，可以通过靶向STAT5B的干预来抑制。STAT5B的阻断可以是PCa的潜在治疗靶标。
