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Abstract：
Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The poor prognosis of this malignancy is attributed mainly to the persistent activation of cancer signaling for metastasis. Here, we showed that protein tyrosine phosphatase-like A domain containing 1 (PTPLAD1) is down-regulated in highly metastatic CRC cells and negatively associated with poor survival of CRC patients. Systematic analysis reveals that epithelial-to-mesenchymal transition (EMT) and mitochondrial fusion-to-fission (MFT) transition are two critical features for CRC patients with low expression of PTPLAD1. PTPLAD1 overexpression suppresses the metastasis of CRC in vivo and in vitro by inhibiting the Raf/ERK signaling-mediated EMT and mitofission. Mechanically, PTPLAD1 binds with PHB via its middle fragment (141-178 amino acids) and induces dephosphorylation of PHB-Y259 to disrupt the interaction of PHB-Raf, resulting in the inactivation of Raf/ERK signaling. Our results unveil a novel mechanism in which Raf/ERK signaling activated in metastatic CRC induces EMT and mitochondrial fission simultaneously, which can be suppressed by PTPLAD1. This finding may provide a new paradigm for developing more effective treatment strategies for CRC.
摘要：
结直肠癌（CRC）仍然是全球癌症相关死亡的主要原因之一。这种恶性肿瘤的不良预后主要归因于用于转移的癌症信号的持续激活。这里,我们发现,蛋白酪氨酸磷酸酶样A结构域包含1(PTPLAD1)在高转移性CRC细胞中下调,并与CRC患者的低生存率负相关.系统分析显示，上皮间质转化（EMT）和线粒体融合分裂（MFT）转化是PTPLAD1低表达的CRC患者的两个关键特征。PTPLAD1过表达通过抑制Raf/ERK信号介导的EMT和有丝分裂在体内和体外抑制CRC的转移。机械上,PTPLAD1通过其中间片段（141-178个氨基酸）与PHB结合，并诱导PHB-Y259的去磷酸化，破坏PHB-Raf的相互作用，导致Raf/ERK信号的失活。我们的研究结果揭示了一种新的机制，即在转移性CRC中激活的Raf/ERK信号同时诱导EMT和线粒体裂变。可以通过PTPLAD1抑制。这一发现可能为开发更有效的CRC治疗策略提供了新的范例。
