PMID- 37124061
OWN - NLM
STAT- MEDLINE
DCOM- 20231028
LR  - 20231028
IS  - 1466-1861 (Electronic)
IS  - 0962-9351 (Print)
IS  - 0962-9351 (Linking)
VI  - 2023
DP  - 2023
TI  - Tumor Necrosis Factor-alpha Promotes the Tumorigenesis, Lymphangiogenesis, and 
      Lymphatic Metastasis in Cervical Cancer via Activating VEGFC-Mediated AKT and ERK 
      Pathways.
PG  - 5679966
LID - 10.1155/2023/5679966 [doi]
LID - 5679966
AB  - BACKGROUND: Lymphatic metastasis is a common phenomenon of cervical cancer. Tumor 
      necrosis factor-alpha (TNF-alpha) was found to be closely associated with lymphatic 
      cancer metastasis. However, the mechanism through which TNF-alpha regulates lymphatic 
      metastasis in cervical cancer remains unclear. METHODS: In this study, cervical 
      cancer cells were cultured in Dulbecco's modified Eagle's medium (DMEM) with or 
      without TNF-alpha for 48 h, and then the corresponding conditional medium (CM-TNF-alpha 
      or CM) was collected. The level of vascular endothelial growth factor (VEGFC) in 
      the corresponding CM was then detected using an enzyme-linked immunosorbent assay 
      (ELISA). Next, human lymphatic endothelial cells (HLECs) were cultured in 
      CM-TNF-alpha or CM for 48 h. Cell viability was measured using the cell counting 
      kit-8 (CCK-8) assay, and angiogenesis was detected using a tube formation assay. 
      Subsequently, the expressions of AKT, p-AKT, ERK, and p-ERK in HLECs were 
      detected using western blotting. In addition, to further investigate the effect 
      of TNF-alpha on the progression of cervical cancer, a C33A subcutaneous xenograft 
      model was established in vivo. RESULTS: We found that TNF-alpha significantly 
      stimulated cervical cancer cells to secrete VEGFC. Additionally, the CM collected 
      from the TNF-alpha-treated cervical cancer cells notably promoted the proliferation, 
      migration, and angiogenesis of HLECs; however, these changes were reversed by 
      MAZ51, a VEGFR3 inhibitor. Moreover, TNF-alpha obviously elevated D2-40 and VEGFC 
      protein expressions in tumor tissues, promoting lymphangiogenesis and lymphatic 
      metastasis in vivo. Meanwhile, TNF-alpha markedly upregulated p-AKT and p-ERK 
      expressions in tumor tissues, whereas these changes were reversed by MAZ51. 
      CONCLUSION: Collectively, TNF-alpha could promote tumorigenesis, lymphangiogenesis, 
      and lymphatic metastasis in vitro and in vivo in cervical cancer via activating 
      VEGFC-mediated AKT and ERK pathways. These results may provide new directions for 
      the treatment of cervical cancer.
CI  - Copyright (c) 2023 Xiao Chen et al.
FAU - Chen, Xiao
AU  - Chen X
AUID- ORCID: 0009-0000-5230-5103
AD  - Department of Gynecology, Clinical Oncology School of Fujian Medical University, 
      Fujian Cancer Hospital, Fuzhou 350000, China.
FAU - Lin, Luping
AU  - Lin L
AUID- ORCID: 0009-0005-5263-1052
AD  - Department of Abdominal Medical Oncology, Clinical Oncology School of Fujian 
      Medical University, Fujian Cancer Hospital, Fuzhou 350000, China.
FAU - Wu, Qiaoling
AU  - Wu Q
AUID- ORCID: 0000-0002-6642-2068
AD  - Department of Gynecology, Clinical Oncology School of Fujian Medical University, 
      Fujian Cancer Hospital, Fuzhou 350000, China.
FAU - Li, Sang
AU  - Li S
AUID- ORCID: 0009-0004-9260-7797
AD  - Department of Gynecology, Clinical Oncology School of Fujian Medical University, 
      Fujian Cancer Hospital, Fuzhou 350000, China.
FAU - Wang, Huihui
AU  - Wang H
AUID- ORCID: 0000-0002-1690-3904
AD  - Wenzhou Central Hospital, The Second Affiliated Hospital of Shanghai University, 
      China.
FAU - Sun, Yang
AU  - Sun Y
AUID- ORCID: 0000-0003-3271-1491
AD  - Department of Gynecology, Clinical Oncology School of Fujian Medical University, 
      Fujian Cancer Hospital, Fuzhou 350000, China.
LA  - eng
PT  - Journal Article
DEP - 20230421
PL  - United States
TA  - Mediators Inflamm
JT  - Mediators of inflammation
JID - 9209001
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factor C)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 0 (VEGFA protein, human)
SB  - IM
MH  - Female
MH  - Humans
MH  - Carcinogenesis/metabolism
MH  - Cell Transformation, Neoplastic/metabolism
MH  - Endothelial Cells/metabolism
MH  - Lymphangiogenesis
MH  - Lymphatic Metastasis/pathology
MH  - MAP Kinase Signaling System
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - *Uterine Cervical Neoplasms/metabolism
MH  - Vascular Endothelial Growth Factor A/metabolism
MH  - Vascular Endothelial Growth Factor C/metabolism
MH  - Vascular Endothelial Growth Factors/metabolism
PMC - PMC10147529
COIS- These authors declared no competing interests in this research.
EDAT- 2023/05/01 06:42
MHDA- 2023/05/02 06:42
PMCR- 2023/04/21
CRDT- 2023/05/01 03:37
PHST- 2022/11/26 00:00 [received]
PHST- 2023/01/14 00:00 [revised]
PHST- 2023/03/31 00:00 [accepted]
PHST- 2023/05/02 06:42 [medline]
PHST- 2023/05/01 06:42 [pubmed]
PHST- 2023/05/01 03:37 [entrez]
PHST- 2023/04/21 00:00 [pmc-release]
AID - 10.1155/2023/5679966 [doi]
PST - epublish
SO  - Mediators Inflamm. 2023 Apr 21;2023:5679966. doi: 10.1155/2023/5679966. 
      eCollection 2023.