PMID- 35025009
OWN - NLM
STAT- MEDLINE
DCOM- 20220316
LR  - 20220531
IS  - 2211-3436 (Electronic)
IS  - 2211-3428 (Linking)
VI  - 45
IP  - 1
DP  - 2022 Feb
TI  - Integrin alpha6 overexpression promotes lymphangiogenesis and lymphatic metastasis 
      via activating the NF-kappaB signaling pathway in lung adenocarcinoma.
PG  - 57-67
LID - 10.1007/s13402-021-00648-3 [doi]
AB  - OBJECTIVE: It has been reported that tumor-associated lymphangiogenesis plays an 
      important role in lymph node metastasis and contributes to the poor survival of 
      lung adenocarcinoma (LUAD) patients. As yet, however, the molecular mechanism 
      underlying LUAD-associated lymphangiogenesis has remained elusive. METHODS: 
      Immunohistochemistry (IHC) was used to determine the expression of integrin 
      subunit alpha 6 (ITGA6) and the lymphatic vessel endothelial hyaluronan receptor 
      1 (Lyve1) in clinicopathologically characterized LUAD specimens. The effect of 
      ITGA6 overexpression on lymphangiogenesis and lymphatic metastasis was examined 
      by tube formation, scratch wound-healing, and cell migration assays in vitro and 
      a popliteal lymph node metastasis model in vivo. Mechanistically, overexpression 
      of ITGA6 and activation of NF-kappaB signaling were examined by real-time PCR, 
      ubiquitination and dual-luciferase reporter assays. Finally, high ITGA6 
      expression in LUAD tissue samples was related to copy number variation (CNV) 
      using the TCGA database. RESULTS: We found that ITGA6 overexpression correlated 
      with microlymphatic vessel density in LUAD specimens (p < 0.01). Importantly, by 
      using a popliteal lymph node metastasis model, we found that ITGA6 upregulation 
      significantly enhanced lymphangiogenesis and lymphatic metastasis in vivo 
      (p < 0.05). In addition, we found that ITGA6 overexpression enhanced the 
      capability of A549 and H1299 LUAD cells to induce tube formation and migration in 
      human lymphatic endothelial cells (HLECs). Mechanistically, we found that ITGA6 
      sustained NF-kappaB activity via binding and promoting K63 polyubiquitination of TNF 
      receptor-associated factor 2 (TRAF2). Finally, CNV analysis revealed ITGA6 
      amplification of 27.5% in the LUAD tissue samples in the TCGA database. 
      CONCLUSIONS: Taken together, our results uncover a plausible role for ITGA6 in 
      mediating lymphangiogenesis and lymphatic metastasis and may provide a basis for 
      targeting ITGA6 to treat LUAD lymphatic metastasis.
CI  - (c) 2021. Springer Nature Switzerland AG.
FAU - Ren, Sijia
AU  - Ren S
AUID- ORCID: 0000-0003-1978-8769
AD  - Taizhou Hospital, Zhejiang University, Taizhou, 317000, China.
FAU - Wang, Jing
AU  - Wang J
AD  - Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, 
      Taizhou, China.
FAU - Xu, Anyi
AU  - Xu A
AD  - Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, 
      Taizhou, China.
FAU - Bao, Jiaqian
AU  - Bao J
AD  - Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, 
      Taizhou, China.
FAU - Cho, William C
AU  - Cho WC
AD  - Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong, 
      China.
FAU - Zhu, Jinrong
AU  - Zhu J
AD  - Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of 
      Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, 
      Guangzhou, China. zhujinrong@gdpu.edu.cn.
FAU - Shen, Jianfei
AU  - Shen J
AD  - Taizhou Hospital, Zhejiang University, Taizhou, 317000, China. 
      jianfei051@163.com.
LA  - eng
GR  - 82002400/national outstanding youth science fund project of national natural 
      science foundation of china/
PT  - Journal Article
DEP - 20220113
PL  - Netherlands
TA  - Cell Oncol (Dordr)
JT  - Cellular oncology (Dordrecht)
JID - 101552938
RN  - 0 (Integrin alpha6)
RN  - 0 (NF-kappa B)
RN  - 0 (Vascular Endothelial Growth Factor C)
SB  - IM
MH  - *Adenocarcinoma of Lung/genetics/metabolism
MH  - Cell Line, Tumor
MH  - DNA Copy Number Variations
MH  - Endothelial Cells/metabolism
MH  - Humans
MH  - Integrin alpha6/metabolism/pharmacology
MH  - *Lung Neoplasms/pathology
MH  - Lymphangiogenesis
MH  - Lymphatic Metastasis
MH  - NF-kappa B/metabolism
MH  - Signal Transduction
MH  - Vascular Endothelial Growth Factor C/genetics/metabolism/pharmacology
OTO - NOTNLM
OT  - Integrin alpha6 (ITGA6)
OT  - Lung adenocarcinoma
OT  - Lymphagiogenesis
OT  - Lymphatic metastasis
OT  - NF-kappaB pathway
EDAT- 2022/01/14 06:00
MHDA- 2022/03/17 06:00
CRDT- 2022/01/13 12:56
PHST- 2021/10/25 00:00 [accepted]
PHST- 2022/01/14 06:00 [pubmed]
PHST- 2022/03/17 06:00 [medline]
PHST- 2022/01/13 12:56 [entrez]
AID - 10.1007/s13402-021-00648-3 [pii]
AID - 10.1007/s13402-021-00648-3 [doi]
PST - ppublish
SO  - Cell Oncol (Dordr). 2022 Feb;45(1):57-67. doi: 10.1007/s13402-021-00648-3. Epub 
      2022 Jan 13.