PMID- 36438491
OWN - NLM
STAT- MEDLINE
DCOM- 20221205
LR  - 20221219
IS  - 1838-7640 (Electronic)
IS  - 1838-7640 (Linking)
VI  - 12
IP  - 17
DP  - 2022
TI  - Elevated ITGA5 facilitates hyperactivated mTORC1-mediated progression of 
      laryngeal squamous cell carcinoma via upregulation of EFNB2.
PG  - 7431-7449
LID - 10.7150/thno.76232 [doi]
AB  - 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.
CI  - (c) The author(s).
FAU - Li, Dapeng
AU  - Li D
AD  - Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated 
      Hospital of Anhui Medical University, Hefei, China.
FAU - Sun, Anjiang
AU  - Sun A
AD  - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui 
      Medical University, Hefei, China.
FAU - Zhang, Liang
AU  - Zhang L
AD  - Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated 
      Hospital of Anhui Medical University, Hefei, China.
FAU - Ding, Zhao
AU  - Ding Z
AD  - Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated 
      Hospital of Anhui Medical University, Hefei, China.
FAU - Yi, Fangzheng
AU  - Yi F
AD  - Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated 
      Hospital of Anhui Medical University, Hefei, China.
FAU - Yang, Xue
AU  - Yang X
AD  - Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated 
      Hospital of Anhui Medical University, Hefei, China.
FAU - Wang, Zixi
AU  - Wang Z
AD  - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui 
      Medical University, Hefei, China.
FAU - Chen, Xu
AU  - Chen X
AD  - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui 
      Medical University, Hefei, China.
FAU - Liu, Weiwei
AU  - Liu W
AD  - Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated 
      Hospital of Anhui Medical University, Hefei, China.
FAU - Liu, Shixian
AU  - Liu S
AD  - Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated 
      Hospital of Anhui Medical University, Hefei, China.
FAU - Shen, Hailong
AU  - Shen H
AD  - Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated 
      Hospital of Anhui Medical University, Hefei, China.
FAU - Miao, Manli
AU  - Miao M
AD  - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui 
      Medical University, Hefei, China.
FAU - Zhang, Ling
AU  - Zhang L
AD  - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui 
      Medical University, Hefei, China.
FAU - Liu, Ping
AU  - Liu P
AD  - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui 
      Medical University, Hefei, China.
FAU - Liu, Yuchen
AU  - Liu Y
AD  - Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated 
      Hospital of Anhui Medical University, Hefei, China.
FAU - Su, Shihong
AU  - Su S
AD  - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui 
      Medical University, Hefei, China.
FAU - Huang, Hailiang
AU  - Huang H
AD  - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui 
      Medical University, Hefei, China.
FAU - Huang, Can
AU  - Huang C
AD  - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui 
      Medical University, Hefei, China.
FAU - Hu, Zhongdong
AU  - Hu Z
AD  - Modern Research Center for Traditional Chinese Medicine, School of Chinese 
      Materia Medica, Beijing University of Chinese Medicine, Beijing, China.
FAU - Zhang, Hongbing
AU  - Zhang H
AD  - 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.
FAU - Zha, Xiaojun
AU  - Zha X
AD  - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui 
      Medical University, Hefei, China.
FAU - Liu, Yehai
AU  - Liu Y
AD  - Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated 
      Hospital of Anhui Medical University, Hefei, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221024
PL  - Australia
TA  - Theranostics
JT  - Theranostics
JID - 101552395
RN  - 0 (EFNB2 protein, human)
RN  - 0 (Ephrin-B2)
RN  - 0 (Integrins)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - 0 (MicroRNAs)
RN  - 0 (ITGA5 protein, human)
RN  - EC 2.7.1.1 (MTOR protein, human)
SB  - IM
MH  - Humans
MH  - *Carcinoma, Squamous Cell/genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/genetics
MH  - *Ephrin-B2/genetics/metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Head and Neck Neoplasms/genetics/metabolism
MH  - *Integrins/genetics/metabolism
MH  - *Laryngeal Neoplasms/genetics
MH  - Mechanistic Target of Rapamycin Complex 1/genetics/metabolism
MH  - MicroRNAs/genetics/metabolism
MH  - *Squamous Cell Carcinoma of Head and Neck/genetics/metabolism
MH  - Up-Regulation
PMC - PMC9691358
OTO - NOTNLM
OT  - EFNB2
OT  - ITGA5
OT  - LSCC
OT  - mTOR
OT  - tumorigenesis
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2022/11/29 06:00
MHDA- 2022/11/30 06:00
PMCR- 2022/01/01
CRDT- 2022/11/28 04:18
PHST- 2022/06/16 00:00 [received]
PHST- 2022/10/10 00:00 [accepted]
PHST- 2022/11/28 04:18 [entrez]
PHST- 2022/11/29 06:00 [pubmed]
PHST- 2022/11/30 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - thnov12p7431 [pii]
AID - 10.7150/thno.76232 [doi]
PST - epublish
SO  - Theranostics. 2022 Oct 24;12(17):7431-7449. doi: 10.7150/thno.76232. eCollection 
      2022.