Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
Int J Biol Sci. 2022 Jul 18;18(13):4869-4883. doi: 10.7150/ijbs.73548. eCollection 2022.
Non-small cell lung cancer (NSCLC) is one of the deadliest cancers in the world. Metastasis is considered one of the leading causes of treatment failure and death in NSCLC patients. A crucial factor of promoting metastasis in epithelium-derived carcinoma has been considered as epithelial-mesenchymal transition (EMT). Rictor, one of the components of mTORC2, has been reportedly involved in EMT and metastasis of human malignancies. However, the regulatory mechanisms of Rictor, Rictor-mediated EMT and metastasis in cancers remain unknown. Our present study indicates that Rictor is highly expressed in human NSCLC cell lines and tissues and is regulated, at least partially, at the transcriptional level. Knockdown of Rictor expression causes phenotype alterations through EMT, which is accompanied by the impairment of migration and invasion ability in NSCLC cells. Additionally, we have cloned and identified the human core promoter for the first time and confirmed that transcription factor KLF4 directly binds to the promoter and transcriptionally upregulated Rictor expression. Knockdown of KLF4 results in Rictor's downregulation accompanied by a series of characteristic changes of mesenchymal-epithelial transition (MET) and significantly decreases migration, invasion as well as metastasis of NSCLC cells. Re-introducing Rictor in KLF4-knockdown NSCLC cells partially reverses the epithelial phenotype to the mesenchymal phenotype and attenuates the inhibition of cell migration and invasion caused by KLF4 knocking down. Knockdown of KLF4 prevents mTOR/Rictor interaction and metastasis of NSCLC . The understanding of the regulator upstream of Rictor may provide an opportunity for the development of new inhibitors and the rational design of combination regimens based on different metastasis-related molecular targets and finally prevents cancer metastasis.
非小细胞肺癌（NSCLC）是世界上最致命的癌症之一。转移被认为是 NSCLC 患者治疗失败和死亡的主要原因之一。促进上皮源性癌转移的一个关键因素被认为是上皮-间充质转化（EMT）。Rictor 是 mTORC2 的一个组成部分，据报道它参与了人类恶性肿瘤的 EMT 和转移。然而，Rictor 的调控机制、Rictor 介导的 EMT 以及癌症转移的机制尚不清楚。我们的研究表明，Rictor 在人非小细胞肺癌细胞系和组织中高表达，并且至少部分受转录水平的调控。敲低 Rictor 的表达会导致 EMT 引起的表型改变，同时伴随着 NSCLC 细胞迁移和侵袭能力的损伤。此外，我们首次克隆并鉴定了人类 Rictor 的核心启动子，并证实转录因子 KLF4 直接结合启动子并转录上调 Rictor 的表达。敲低 KLF4 导致 Rictor 的下调，伴随着一系列典型的间充质-上皮转化（MET）特征性改变，并显著降低 NSCLC 细胞的迁移、侵袭和转移。在 KLF4 敲低的 NSCLC 细胞中重新引入 Rictor，部分逆转上皮表型为间充质表型，并减弱 KLF4 敲低引起的细胞迁移和侵袭抑制。敲低 KLF4 可防止 mTOR/Rictor 相互作用和 NSCLC 的转移。了解 Rictor 的上游调控因子可能为开发新的抑制剂和基于不同转移相关分子靶点的联合治疗方案提供机会，最终阻止癌症转移。
