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Theranostics 2022; 12(17):7431-7449. doi:10.7150/thno.76232 This issue Cite

Research Paper

Elevated ITGA5 facilitates hyperactivated mTORC1-mediated progression of laryngeal squamous cell carcinoma via upregulation of EFNB2

Dapeng Li1*, Anjiang Sun2*, Liang Zhang1*, Zhao Ding1*, Fangzheng Yi1, Xue Yang1, Zixi Wang2, Xu Chen2, Weiwei Liu1, Shixian Liu1, Hailong Shen1, Manli Miao2, Ling Zhang2, Ping Liu2, Yuchen Liu1, Shihong Su2, Hailiang Huang2, Can Huang2, Zhongdong Hu4, Hongbing Zhang3✉, Xiaojun Zha2✉, Yehai Liu1✉

1. Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
2. Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.
3. State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
4. Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Yehai Liu, M.D, Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China. Address: No. 218 Jixi Road, Hefei 230000, Anhui Province, China. E-mail: liuy More

Citation:
Li D, Sun A, Zhang L, Ding Z, Yi F, Yang X, Wang Z, Chen X, Liu W, Liu S, Shen H, Miao M, Zhang L, Liu P, Liu Y, Su S, Huang H, Huang C, Hu Z, Zhang H, Zha X, Liu Y. Elevated ITGA5 facilitates hyperactivated mTORC1-mediated progression of laryngeal squamous cell carcinoma via upregulation of EFNB2. Theranostics 2022; 12(17):7431-7449. doi:10.7150/thno.76232. https://www.thno.org/v12p7431.htm
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Abstract

Graphic 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.

Results: We successfully established a novel LSCC cell line with hyperactivated mTORC1 activity and then identified integrin subunit alpha 5 (ITGA5) as a novel functional downstream effector of mTORC1 in the progression of LSCC. Elevated ITGA5 promotes LSCC progression through augmentation of ephrin-B2 (EFNB2). Clinical data analysis indicated that the activation of the mTORC1-ITGA5-EFNB2 signaling pathway is associated with malignant progression and poor prognosis of LSCC patients. Inhibition of ITGA5 significantly sensitized LSCC cells to CDDP.

Conclusions: Our findings highlight a novel molecular mechanism for the tumorigenesis driven by deregulated mTORC1 signaling in LSCC, suggesting that the ITGA5-EFNB2 axis may be a therapeutic target for the treatment of mTORC1-related LSCC.

Keywords: mTOR, ITGA5, EFNB2, LSCC, tumorigenesis

Citation styles

APA
Li, D., Sun, A., Zhang, L., Ding, Z., Yi, F., Yang, X., Wang, Z., Chen, X., Liu, W., Liu, S., Shen, H., Miao, M., Zhang, L., Liu, P., Liu, Y., Su, S., Huang, H., Huang, C., Hu, Z., Zhang, H., Zha, X., Liu, Y. (2022). Elevated ITGA5 facilitates hyperactivated mTORC1-mediated progression of laryngeal squamous cell carcinoma via upregulation of EFNB2. Theranostics, 12(17), 7431-7449. https://doi.org/10.7150/thno.76232.

ACS
Li, D.; Sun, A.; Zhang, L.; Ding, Z.; Yi, F.; Yang, X.; Wang, Z.; Chen, X.; Liu, W.; Liu, S.; Shen, H.; Miao, M.; Zhang, L.; Liu, P.; Liu, Y.; Su, S.; Huang, H.; Huang, C.; Hu, Z.; Zhang, H.; Zha, X.; Liu, Y. Elevated ITGA5 facilitates hyperactivated mTORC1-mediated progression of laryngeal squamous cell carcinoma via upregulation of EFNB2. Theranostics 2022, 12 (17), 7431-7449. DOI: 10.7150/thno.76232.

NLM
Li D, Sun A, Zhang L, Ding Z, Yi F, Yang X, Wang Z, Chen X, Liu W, Liu S, Shen H, Miao M, Zhang L, Liu P, Liu Y, Su S, Huang H, Huang C, Hu Z, Zhang H, Zha X, Liu Y. Elevated ITGA5 facilitates hyperactivated mTORC1-mediated progression of laryngeal squamous cell carcinoma via upregulation of EFNB2. Theranostics 2022; 12(17):7431-7449. doi:10.7150/thno.76232. https://www.thno.org/v12p7431.htm

CSE
Li D, Sun A, Zhang L, Ding Z, Yi F, Yang X, Wang Z, Chen X, Liu W, Liu S, Shen H, Miao M, Zhang L, Liu P, Liu Y, Su S, Huang H, Huang C, Hu Z, Zhang H, Zha X, Liu Y. 2022. Elevated ITGA5 facilitates hyperactivated mTORC1-mediated progression of laryngeal squamous cell carcinoma via upregulation of EFNB2. Theranostics. 12(17):7431-7449.

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