Dataset Information

LncRNA HOTTIP facilitates the stemness of breast cancer via regulation of miR-148a-3p/WNT1 pathway.

ABSTRACT: Emerging evidence suggests that dysregulation of long non-coding RNA (lncRNA) plays a key role in tumorigenesis. The lncRNA, HOXA transcript at the distal tip (HOTTIP), has been reported to be up-regulated in multiple cancers, including breast cancer, and is involved in various biological processes, including the maintenance of stemness. However, the biological function and underlying modulatory mechanism of HOTTIP in breast cancer stem cells (BCSCs) remains unknown. In this study, we found that HOTTIP was markedly up-regulated in BCSCs and had a positive correlation with breast cancer progression. Functional studies revealed that overexpression of HOTTIP markedly promoted cell clonogenicity, increased the expression of the stem cell markers, OCT4 and SOX2, and decreased the expression of the differentiation markers, CK14 and CK18, in breast cancer cells. Knockdown of HOTTIP inhibited the CSC-like properties of BCSCs. Consistently, depletion of HOTTIP suppressed tumour growth in a humanized model of breast cancer. Mechanistic studies demonstrated that HOTTIP directly binds to miR-148a-3p and inhibits the mediation of WNT1, which leads to inactivation of the Wnt/?-catenin signalling pathway. Our study is the first to report that HOTTIP regulates the CSC-like properties of BCSCs by as a molecular sponge for miR-148a-3p to increase WNT1 expression, offering a new target for breast cancer therapy.

SUBMITTER: Han L

PROVIDER: S-EPMC7294123 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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LncRNA HOTTIP facilitates the stemness of breast cancer via regulation of miR-148a-3p/WNT1 pathway.

Han Li L Yan Yuanyuan Y Zhao Lin L Liu Yinuo Y Lv Xuemei X Zhang Liwen L Zhao Yanyun Y Zhao Haishan H He Miao M Wei Minjie M

Journal of cellular and molecular medicine 20200419 11

Emerging evidence suggests that dysregulation of long non-coding RNA (lncRNA) plays a key role in tumorigenesis. The lncRNA, HOXA transcript at the distal tip (HOTTIP), has been reported to be up-regulated in multiple cancers, including breast cancer, and is involved in various biological processes, including the maintenance of stemness. However, the biological function and underlying modulatory mechanism of HOTTIP in breast cancer stem cells (BCSCs) remains unknown. In this study, we found that ...[more]

PMID: 32307830

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Project description:BackgroundNon-small cell lung cancer (NSCLC) is a major cause of cancer-related death worldwide, and cancer stem cell is responsible for the poor clinical outcome of NSCLC. Previous reports indicated that long noncoding RNAs (lncRNAs) play important roles in maintaining cancer stemness, however, the underlying mechanisms remain unclear. This study investigates the role of ASAP1 Intronic Transcript 1 (ASAP1-IT1) in cancer cell stemness of NSCLC.MethodsThe expression of ASAP1-IT1, microRNA-509-3p (miR-509-3p) and apoptosis-/stemness-related genes was analyzed by qRT-PCR in NSCLC tissues, cancer cells and spheres of cancer stem cells. Knockdown of ASAP1-IT1 or overexpression of miR-509-3p in NSCLC cells by infection or transfection of respective plasmids. Sphere formation and colony formation were used to detect NSCLC stem cell-like properties and tumor growth in vitro. Luciferase reporter assays, RNA immunoprecitation (RIP) and qRT-PCR assays were used to analyze the interaction between lncRNA and miRNA. The expression of expression of regulated genes of ASAP1-IT1/miR-509-3p axis was evaluated by qRT-PCR and Western blot. The NSCLC xenograft mouse model was used to validate the role of ASAP1-IT1 in NSCLC stemness and tumor growth in vivo.ResultsASAP1-IT1 was up-regulated in NSCLC tissues, cancer cells, and in spheres of A549-derived cancer stem cells. Downregulation of ASAP1-IT1 or overexpression of miR-509-3p significantly decreased cell colony formation and stem cell-like properties of A549-dereived stem cells with decreased expression of stem cell biomarkers SOX2, CD34, and CD133, and suppressing the expression of cell growth-related genes, Cyclin A1, Cyclin B1, and PCNA. Furthermore, knockdown of ASAP1-IT1 or overexpression of miR-509-3p repressed tumor growth in nude mice via reducing expression of tumorigenic genes. ASAP1-IT1 was found to interact with miR-509-3p. Moreover, overexpression of ASAP1-IT1 blocked the inhibition by miR-509-3p on stem cell-like properties and cell growth of A549-dereived stem cells both in vitro and in vivo. Finally, the level of YAP1 was regulated by ASAP1-IT1 and miR-509-3p.ConclusionsYAP1-involved ASAP1-IT1/miR-509-3p axis promoted NSCLC progression by regulating cancer cell stemness, and targeting this signaling pathway could be is a promising therapeutic strategy to overcome NSCLC stemness.

Dataset Information

LncRNA HOTTIP facilitates the stemness of breast cancer via regulation of miR-148a-3p/WNT1 pathway.

Publications

LncRNA HOTTIP facilitates the stemness of breast cancer via regulation of miR-148a-3p/WNT1 pathway.

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