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食管癌细胞分泌的外泌体 uc.189 促进淋巴转移。

Esophageal carcinoma cell-excreted exosomal uc.189 promotes lymphatic metastasis.

机构信息

Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225009, PR China.

Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225001, PR China.

出版信息

Aging (Albany NY). 2021 May 23;13(10):13846-13858. doi: 10.18632/aging.202979.

DOI:10.18632/aging.202979
PMID:34024769
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8202844/
Abstract

Most cancers are old age-related diseases. Patients with lymphatic metastasis have an extremely poor prognosis in esophageal cancers (ECs). Previous studies showed ultraconserved RNAs are involved in tumorigenesis and ultraconserved RNA 189 (uc.189) served as an oncogene in cervical cancer, but the effect of exosomal uc.189 in esophageal squamous cell carcinoma (ESCC) remains undefined. This study revealed that uc.189 is closely correlated with lymph node (LN) metastasis and the number of lymphatic vessels in ESCC. ESCC-secreted exosomal uc.189 is transferred into human lymphatic endothelial cells (HLECs) to promote its proliferation, migration and tube formation to facilitate lymph node metastasis. Mechanistically, uc.189 regulated EPHA2 expression by directly binding to its 3'UTR region through dual-luciferase reporter assay. Over-expression and knockdown of EPHA2 could respectively rescue and simulate the effects induced by exosomal uc.189. Especially, the uc.189-EPHA2 axis activates the P38MAPK/VEGF-C pathway in HLECs. Finally, ESCC-secreted exosomal of uc.189 promotes HLECs sprouting , migration, and lymphangiogenesis. Thus, these findings suggested that exosomal uc.189 targets the EPHA2 of HLECs to promote lymphangiogenesis, and may represent a novel marker of diagnosis and treatment for ESCC patients in early stages.

摘要

大多数癌症是与年龄相关的疾病。患有淋巴转移的食管癌（ECs）患者预后极差。先前的研究表明，超保守 RNA 参与肿瘤发生，超保守 RNA 189（uc.189）在宫颈癌中作为癌基因发挥作用，但外泌体 uc.189 在食管鳞状细胞癌（ESCC）中的作用仍未确定。本研究表明，uc.189 与 ESCC 的淋巴结（LN）转移和淋巴管数量密切相关。ESCC 分泌的外泌体 uc.189 转移到人淋巴管内皮细胞（HLECs）中，促进其增殖、迁移和管形成，从而促进淋巴结转移。在机制上，uc.189 通过双荧光素酶报告基因检测直接与其 3'UTR 区域结合来调节 EPHA2 的表达。过表达和敲低 EPHA2 可分别挽救和模拟外泌体 uc.189 诱导的作用。特别是，uc.189-EPHA2 轴在 HLECs 中激活 P38MAPK/VEGF-C 通路。最后，ESCC 分泌的外泌体 uc.189 促进 HLECs 出芽、迁移和淋巴管生成。因此，这些发现表明外泌体 uc.189 靶向 HLECs 的 EPHA2 促进淋巴管生成，可能代表 ESCC 患者早期诊断和治疗的新标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/8c1a32b6f11e/aging-13-202979-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/34cd556e75b6/aging-13-202979-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/5041498f2282/aging-13-202979-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/17d6079f22b0/aging-13-202979-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/99370e58d354/aging-13-202979-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/64e2be9043e7/aging-13-202979-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/59f271d06b42/aging-13-202979-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/8c1a32b6f11e/aging-13-202979-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/34cd556e75b6/aging-13-202979-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/5041498f2282/aging-13-202979-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/17d6079f22b0/aging-13-202979-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/99370e58d354/aging-13-202979-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/64e2be9043e7/aging-13-202979-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/59f271d06b42/aging-13-202979-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1e6/8202844/8c1a32b6f11e/aging-13-202979-g007.jpg

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