In prostate cancer (PCa) patients, a proto-oncogene Tumor protein D52 (TPD52) is overexpressed, and it is involved in different cellular functions. In this study, we report that TPD52 expression is positively associated with the emergence of neuroendocrine PCa (NEPC). With overexpression of TPD52 in LNCaP cells, we found neuroendocrine differentiation (NED) of cells in in-vitro and distinct NED features confirmed by NE markers neuron-specific enolase (NSE) and chromogranin A (CHR-A). Further, we investigated the molecular mechanisms involved in TPD52 mediated NED of PCa cells. We found that TPD52 activates the NF- κB – STAT3 axis for the induction of NED in LNCaP cells. Indeed, inhibition of NF-κB – STAT3 attenuated the progression of NED in TPD52 positive LNCaP cells. Importantly, silencing of TPD52 expression or inhibition of NF-κB – STAT3 activity in a neuroendocrine cell line NCI-H660 showed a marked decrease in the expression of NSE and CHR-A, confirming the reversal of the NE properties. Notably, TPD52 overexpression in LNCaP cells induced expression of N-cadherin, Vimentin, ZEB1, and Snail1 indicating that TPD52 positively regulates epithelial to mesenchymal transition (EMT) of PCa cells towards NED. Moreover, silencing of Snail1 in TPD52 positive cells blocked the progression of NED and, in NCI-H660 cells reversed NE properties as expected. Of the few requirements of TPD52, activation of NF-κB – STAT3 is essential for promoting EMT compelling NED of LNCaP cells. Collectively, these results reveal that TPD52 is associated with the progression of NEPC and emphasizes the need for therapeutic targeting of TPD52 in PCa.

在前列腺癌 (PCa) 患者中，原癌基因肿瘤蛋白 D52 (TPD52)过度表达，并且参与不同的细胞功能。在这项研究中，我们报告 TPD52 表达与神经内分泌 PCa (NEPC) 的出现呈正相关。随着 LNCaP 细胞中 TPD52 的过度表达，我们在体外发现了细胞的神经内分泌分化 (NED)，并且通过 NE 标记物神经元特异性烯醇化酶 (NSE) 和嗜铬粒蛋白 A (CHR-A) 证实了不同的 NED 特征。此外，我们研究了 TPD52 介导 PCa 细胞 NED 的分子机制。我们发现 TPD52 激活 NF-κB – STAT3 轴以诱导 LNCaP 细胞中的 NED。事实上，抑制 NF-κB – STAT3 可以减弱 TPD52 阳性 LNCaP 细胞中 NED 的进展。重要的是，在神经内分泌细胞系NCI-H660中沉默TPD52表达或抑制NF-κB – STAT3活性显示NSE和CHR-A表达显着降低，证实了NE特性的逆转。值得注意的是，TPD52 在 LNCaP 细胞中过表达会诱导 N-钙粘蛋白、波形蛋白、ZEB1 和 Snail1 的表达，表明 TPD52 正向调节 PCa 细胞向 NED 的上皮间质转化 (EMT)。此外，在 TPD52 阳性细胞中沉默 Snail1 可以阻止 NED 的进展，并且在 NCI-H660 细胞中，如预期的那样逆转了 NE 特性。在 TPD52 的少数要求中，NF-κB – STAT3 的激活对于促进 LNCaP 细胞的 EMT 强制 NED 至关重要。总的来说，这些结果揭示了 TPD52 与 NEPC 的进展相关，并强调了 PCa 中 TPD52 治疗靶向的必要性。