Tumor Necrosis Factor- α Promotes the Tumorigenesis, Lymphangiogenesis, and Lymphatic Metastasis in Cervical Cancer via Activating VEGFC-Mediated AKT and ERK Pathways
- Mediators Inflamm. 2023 Apr 21:2023:5679966. doi: 10.1155/2023/5679966.
- 1. Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350000, China.
- 2. Department of Abdominal Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350000, China.
- 3. Wenzhou Central Hospital, The Second Affiliated Hospital of Shanghai University, China.
Background: Lymphatic metastasis is a common phenomenon of cervical Cancer. Tumor necrosis factor-α (TNF-α) was found to be closely associated with lymphatic Cancer metastasis. However, the mechanism through which TNF-α 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-α for 48 h, and then the corresponding conditional medium (CM-TNF-α 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-α 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-α on the progression of cervical Cancer, a C33A subcutaneous xenograft model was established in vivo.
Results: We found that TNF-α significantly stimulated cervical Cancer cells to secrete VEGFC. Additionally, the CM collected from the TNF-α-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-α obviously elevated D2-40 and VEGFC protein expressions in tumor tissues, promoting lymphangiogenesis and lymphatic metastasis in vivo. Meanwhile, TNF-α markedly upregulated p-AKT and p-ERK expressions in tumor tissues, whereas these changes were reversed by MAZ51.
Conclusion: Collectively, TNF-α 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.