Deregulation of TGF-β signaling is intricately engrossed in the pathophysiology of pancreatic adenocarcinomas (PDACs). The role of TGF-β all through pancreatic cancer initiation and progression is multifarious and somewhat paradoxical. TGF-β plays a tumor suppressive role in early-stage pancreatic cancer by promoting apoptosis and inhibiting epithelial cell cycle progression, but incites tumor promotion in late-stage by modulating genomic instability, neo-angiogenesis, immune evasion, cell motility, and metastasis. Here, we provide evidences that Par-4 acts as one of the vital mediators to regulate TGF-β/Smad4 pathway, wherein, Par-4 induction/over-expression induced EMT which was later culminated in to apoptosis in presence of TGF-β via positive regulation of Smad4. Intriguingly, Par-4-/- cells were devoid of significant Smad4 induction compared to Par-4+/+ cells in presence of TGF-β and ectopic Par-4 steadily augmented Smad4 expression by restoring TGF-β/Smad4 axis in Panc-1 cells. Further, our FACS and western blotting results unveiled that Par-4 dragged the PDAC cells to G1 arrest in presence of TGF-β byelevating p21 and p27 levels while attenuating Cyclin E and A levels and augmenting caspase 3 cleavage triggering lethal EMT. Through restoration of Smad4, we further establish that in BxPC3 cell line (Smad4-/-), Smad4 is essential for Par-4 to indulge TGF-β dependent lethal EMT program. The mechanistic relevance of Par-4 mediated Smad4 activation was additionally validated by co-immunoprecipitation wherein disruption of NM23H1-STRAP interaction by Par-4 rescues TGF-β/Smad4 pathway in PDAC and mediates the tumor suppressive role of TGF-β, therefore serving as a vital cog to restore the apoptotic functions of TGF-β pathway.

中文翻译：

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PDAC细胞中Par-4介导的Smad4诱导恢复了正常的TGF-β/ Smad4轴，从而驱动细胞向致死性EMT方向发展。

胰腺腺癌（PDAC）的病理生理完全涉及TGF-β信号的失调。TGF-β在整个胰腺癌的发生和发展过程中的作用多种多样，有些自相矛盾。TGF-β通过促进细胞凋亡和抑制上皮细胞周期进程在早期胰腺癌中发挥肿瘤抑制作用，但通过调节基因组不稳定性，新血管生成，免疫逃逸，细胞运动和转移，在晚期胰腺癌中发挥促进作用。在这里，我们提供的证据表明，Par-4是调节TGF-β/ Smad4通路的重要介质之一，其中，Par-4诱导/过表达诱导的EMT，后来在TGF-β存在下最终导致细胞凋亡。通过对Smad4的积极调控。有趣的是 与存在TGF-β的Par-4 + / +细胞相比，Par-4-/-细胞缺乏明显的Smad4诱导作用，而异位Par-4通过在Panc-1细胞中恢复TGF-β/ Smad4轴而稳定地增强了Smad4的表达。 。此外，我们的FACS和Western印迹结果表明，在TGF-β存在的情况下，Par-4通过升高p21和p27的水平，同时减弱Cyclin E和A的水平以及增强caspase 3裂解来触发致命的EMT，将PDAC细胞拖至G1阻滞。通过恢复Smad4，我们进一步确定在BxPC3细胞系（Smad4-/-）中，Smad4对于Par-4放纵TGF-β依赖性致死性EMT程序至关重要。