Abstract 1486: Exosomal miR-141 promoted tumor angiogenesis via KLF12 in small cell lung cancer

Abstract

Abstract Background: Angiogenesis, the basic requirement for the survival of tumor cells, has been considered to be one of the malignant characteristics of small cell lung cancer (SCLC) and was closely related to the poor outcomes of SCLC patients. MiR-141 has been found to play a pro- or anti-angiogenetic role in different cancers while its role in SCLC angiogenesis has never been explored. Methods: We isolate total RNA from plasm exosomes and serum samples from two cohorts of SCLC patients respectively to detect the expression of circulating miR-141 in SCLC patients using qRT-PCR. miR-141 was overexpressed in SCLC cell-secreted exosomes to investigate its effects on cell migration, tube formation and microvessel sprouting capabilities of human umbilical vein vascular endothelial cells (HUVECs) both in vitro and in vivo. A dual-luciferase assay was conducted to validate the direct target gene of miR-141. Results: We showed that the level of circulating miR-141 was significantly upregulated in a total of 116 SCLC patients compared with normal volunteers, and the increased miR-141 was revealed to be associated with advanced patient TNM stages which implying the potential oncogenic role of miR-141 in SCLC malignances. In vitro experiments indicated that miR-141 was packaged into SCLC cell-secreted exosomes and was delivered to HUVECs via exosomes to strengthen the migration, invasion, tube formation and microvessel sprouting capabilities of HUVECs. Moreover, mouse models demonstrated that exosomal miR-141 derived from SCLC cells induced neo-angiogenesis in vivo and subcutaneous tumor nodules developed from SCLC cells with miR-141 overexpression showed higher microvessel densities and faster tumor growth than which developed from negative control cells. Combining miRNA target prediction tools with a dual-luciferase assay, we identified that KLF12 was the direct target gene of miR-141 and the angiogenetic promotion effect of miR-141 on HUVECs was abrogated by overexpressing KLF12. Conclusions: Our results elaborated the specific function of exosomal miR-141/KLF12 pathway in SCLC angiogenesis for the first time and provided potential novel targets for anti-angiogenetic therapies in SCLC patients. Our study highlighted the critical role of exosomal miRNAs in SCLC microenvironments and cell communications which offered novel clues for the future exploration of molecular mechanisms of SCLC malignances. Citation Format: Shuangshuang Mao, Zhiliang Lu, Sufei Zheng, Guochao Zhang, Jianbing Huang, Nan Sun, Jie He. Exosomal miR-141 promoted tumor angiogenesis via KLF12 in small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1486.