Sema4C modulates the migration of primary tumor‑associated lymphatic endothelial cells via an ERK‑mediated pathway

Abstract

Although lymphatic endothelial cells (LECs) serve a positive role in tumor lymphatic metastasis, the regulation of LECs undergoing migration similar to that of tumor cells remains poorly understood. A previous study revealed that semaphorin 4C (Sema4C) could be a marker of LECs in cervical cancer. Thus, the present study aimed to understand the mechanism via which Sema4C could promote the development of tumor-associated characteristics in LECs in cervical cancer. Primary tumor-associated LECs (TLECs) were distinguished from cervical cancer by flow cytometry. The promigratory ability was assessed using the Transwell assay. Lentivirus infection was used to alter the expression of Sema4C in TLECs. Confocal laser scanning was used to determine the infection efficiency of lentivirus infection. Sema4C/ERK/E-cadherin pathway was measured by reverse transcription-quantitative PCR and western blotting. The co-localization of Sema4C and the lymphatic marker lymphatic vessel endothelial hyaluronan receptor 1 was verified. Primary tumor-associated LECs (TLECs) were isolated from a mouse xenograft cervical tumor model. It was revealed that overexpressing Sema4C stimulated the migratory ability of TLECs, downregulated E-cadherin expression and stimulated ERK phosphorylation, whereas knocking down Sema4C had the opposite effects. The treatment of PD98059 (ERK inhibitor) blocked the pro-migratory ability of TLECs, which indicated a dependence on the ERK signaling pathway. It was identified that the Sema4C/ERK/E-cadherin pathway may be critical for the migration of TLECs, which may promote lymph node metastasis. Therefore, Sema4C could be a promising target for the treatment of cervical cancer with lymphatic metastasis.

Tumor microenvironment promotes lymphatic metastasis of cervical cancer: its mechanisms and clinical implications

“…Although most patients with early-stage CC recover well through surgery, patients with recurrent or metastatic CC are rarely treated effectively ( 2 , 3 ). Therefore, patients with advanced CC have a poor prognosis and low survival rate ( 4 , 5 ). Lymphatic vessels are one of the crucial routes by which CC cells metastasize, and treatment failure is often associated with lymph node metastasis ( 6 ).…”

Cervical Cancer Imaging Features Associated With ADRB1 as a Risk Factor for Cerebral Neurovascular Metastases

“…Cervical cancer metastasis occurs mainly via the lymphatic route ( 10 ). The most common sites of distant metastases are the lungs, bones, and liver, in order of priority ( 11 ).…”