Elevated ITGA5 facilitates hyperactivated mTORC1-mediated progression of laryngeal squamous cell carcinoma via upregulation of EFNB2
Dapeng Li, Anjiang Sun, Liang Zhang, Zhao Ding, Fangzheng Yi, Xue Yang, Zixi Wang, Xu Chen, Weiwei Liu, Shixian Liu, Hailong Shen, Manli Miao, Ling Zhang, Ping Liu, Yuchen Liu, Shihong Su, Hailiang Huang, Can Huang, Zhongdong Hu, Hongbing Zhang, Xiaojun Zha, Yehai Liu
Abstract
Background: Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors of the head and neck, and it has shown increasing incidence and mortality. The mechanistic target of rapamycin complex 1 (mTORC1) is frequently dysregulated in LSCC, but its underlying mechanisms remain unclear. Methods: Establishment of a novel LSCC cell line using primary LSCC tumor tissues with dysregulated mTORC1 activity and then stable knockdown of Raptor (an mTORC1 specific component) in this cell line. Transcriptomic sequencing, quantitative real-time PCR, western blot analysis, and immunofluorescence assays were used to identify the crucial downstream effector of mTORC1. A series of experiments were conducted to investigate the functions and underlying mechanisms of the mTORC1 target gene in LSCC progression. Clinical LSCC samples were used to evaluate the association of mTORC1 and its downstream targets with clinicopathological features and patient prognosis. Finally, the influence on cisplatin (CDDP) sensitivity upon depletion of the mTORC1 target gene was assessed using a cell culture system, a cell line-derived xenograft (CDX) model, and a patient-derived xenograft (PDX) model.