Abstract
Cancer-secreted exosomal miRNAs are emerging mediators of cancer-stromal cross-talk in the tumor environment. Our previous miRNAs array of cervical squamous cell carcinoma (CSCC) clinical specimens identified upregulation of miR-221-3p. Here, we show that miR-221-3p is closely correlated with peritumoral lymphangiogenesis and lymph node (LN) metastasis in CSCC. More importantly, miR-221-3p is characteristically enriched in and transferred by CSCC-secreted exosomes into human lymphatic endothelial cells (HLECs) to promote HLECs migration and tube formation in vitro, and facilitate lymphangiogenesis and LN metastasis in vivo according to both gain-of-function and loss-of-function experiments. Furthermore, we identify vasohibin-1 (VASH1) as a novel direct target of miR-221-3p through bioinformatic target prediction and luciferase reporter assay. Re-expression and knockdown of VASH1 could respectively rescue and simulate the effects induced by exosomal miR-221-3p. Importantly, the miR-221-3p-VASH1 axis activates the ERK/AKT pathway in HLECs independent of VEGF-C. Finally, circulating exosomal miR-221-3p levels also have biological function in promoting HLECs sprouting in vitro and are closely associated with tumor miR-221-3p expression, lymphatic VASH1 expression, lymphangiogenesis, and LN metastasis in CSCC patients. In conclusion, CSCC-secreted exosomal miR-221-3p transfers into HLECs to promote lymphangiogenesis and lymphatic metastasis via downregulation of VASH1 and may represent a novel diagnostic biomarker and therapeutic target for metastatic CSCC patients in early stages.
Highlights
These authors contributed : Chen-Fei Zhou, Jing Ma, Lei HuangElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Cervical squamous cell carcinoma (CSCC) is one of the most prevalent malignancies, and its incidence in female malignancies worldwide is ~ 15% [1]
In addition to tumor cells, high miR-221-3p levels were present in some peritumoral lymphatic vessels. These results suggested that high levels of miR-221-3p expression may promote lymphangiogenesis and facilitate lymphatic metastasis in CSCC
Our clinical evidence revealed that circulating exosomal miR-221-3p promoted lymphangiogenesis in vitro and was associated with peritumoral lymphatic vessel density (PLVD) and lymph node (LN) metastasis in patients with CSCC, suggesting that circulating exosomal miR-221-3p may serve as a diagnostic biomarker and therapeutic target for metastatic CSCC
Summary
Cervical squamous cell carcinoma (CSCC) is one of the most prevalent malignancies, and its incidence in female malignancies worldwide is ~ 15% [1]. As the major spreading route, lymphatic metastasis is an Cervical squamous cell carcinoma-secreted exosomal miR-221-3p promotes lymphangiogenesis and lymphatic. Among multiple factors underlying lymphatic metastasis, the adaptation of the primary tumor microenvironment by cancer to facilitate tumor cell dissemination plays an important prometastatic role [6]. Lymphangiogenesis is the process of growing new lymphatic vessels and correlates with the incidence of lymphatic metastasis and poor prognosis in multiple cancers [7,8,9]. Growing evidence revealed that lymphatic vessels in the tumor periphery served as a highway for tumor cells to disseminate from their primary site to regional lymph nodes (LNs) [10, 11]. The molecular mechanism of tumor-driven peritumoral lymphangiogenesis is not well defined
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