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YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression.

ABSTRACT: Hypoxia occurs naturally at high-altitudes and pathologically in hypoxic solid tumors. Here, we report that genes involved in various human cancers evolved rapidly in Tibetans and six Tibetan domestic mammals compared to reciprocal lowlanders. Furthermore, m6A modified mRNA binding protein YTHDF1, one of evolutionary positively selected genes for high-altitude adaptation is amplified in various cancers, including non-small cell lung cancer (NSCLC). We show that YTHDF1 deficiency inhibits NSCLC cell proliferation and xenograft tumor formation through regulating the translational efficiency of CDK2, CDK4, and cyclin D1, and that YTHDF1 depletion restrains de novo lung adenocarcinomas (ADC) progression. However, we observe that YTHDF1 high expression correlates with better clinical outcome, with its depletion rendering cancerous cells resistant to cisplatin (DDP) treatment. Mechanistic studies identified the Keap1-Nrf2-AKR1C1 axis as the downstream mediator of YTHDF1. Together, these findings highlight the critical role of YTHDF1 in both hypoxia adaptation and pathogenesis of NSCLC.

SUBMITTER: Shi Y

PROVIDER: S-EPMC6814821 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression.

Shi Yulin Y Fan Songqing S Wu Mengge M Zuo Zhixiang Z Li Xingyang X Jiang Liping L Shen Qiushuo Q Xu Peifang P Zeng Lin L Zhou Yongchun Y Huang Yunchao Y Yang Zuozhang Z Zhou Jumin J Gao Jing J Zhou Hu H Xu Shuhua S Ji Hongbin H Shi Peng P Wu Dong-Dong DD Yang Cuiping C Chen Yongbin Y

Nature communications 20191025 1

Hypoxia occurs naturally at high-altitudes and pathologically in hypoxic solid tumors. Here, we report that genes involved in various human cancers evolved rapidly in Tibetans and six Tibetan domestic mammals compared to reciprocal lowlanders. Furthermore, m<sup>6</sup>A modified mRNA binding protein YTHDF1, one of evolutionary positively selected genes for high-altitude adaptation is amplified in various cancers, including non-small cell lung cancer (NSCLC). We show that YTHDF1 deficiency inhib ...[more]

PMID: 31653849

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Project description:BackgroundAccumulating evidence highlights the critical roles of fibroblast growth factors (FGFs) in regulating the progression of multiple human cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the role of FGF11 in the progression of NSCLC.MethodsPreviously published transcriptomic data (GSE75037 and GSE81089) were used to compare FGF11 expression level between NSCLC tumor tissues and adjacent normal tissues. 100 cases of NSCLC tumor tissues and 30 cases of matched adjacent normal tissues were used to validate FGF11 expression at mRNA and protein level by qPCR and immunohistochemistry. Bioinformatics analysis and dual luciferase reporter analysis were performed to confirm the regulatory effect of miR-525-5p on FGF11 expression. CCK-8 assay and transwell migration assay were employed to examine cellular proliferation, migration and invasion. Gene set enrichment analysis (GSEA) was performed to identify the signaling pathway associated with FGF11 expression. Finally, the functional role of FGF11 in NSCLC tumor growth was evaluated by in vivo study.ResultsFGF11 was upregulated in NSCLC tumor tissues and tumor cell lines. High FGF11 expression was associated with a poor prognosis in NSCLC patients. In vitro loss- and gain-of function experiments demonstrated that FGF11 knockdown inhibited, whereas FGF11 overexpression promoted the proliferation, migration and invasion of NSCLC cells. Dual luciferase reporter assay confirmed that FGF11 was downregulated by miR-525-5p, and the effect of FGF11 on cell proliferation, migration and invasion could be interfered by miR-525-5p. GSEA analysis further revealed that FGF11 expression was enriched with genes in hypoxia signaling pathway and the oncogenic function of FGF11 could be suppressed by knocking down HIF-1α in NSCLC cells. Moreover, FGF11 knockdown suppressed NSCLC tumor growth whereas FGF11 overexpression promoted tumor growth in vivo.ConclusionsOur study showed that FGF11 functions as an oncogene in tumor NSCLC progression. miR-525-5p seems to negatively regulate FGF11 and the oncogenic role of FGF11 is dependent on the upregulation of HIF-1α. Our study suggests that targeting FGF11 and HIF-1α may serve as novel strategies for the treatment of NSCLC.

Project description:The tumor microenvironment, including stroma cells, signaling molecules, and the extracellular matrix, critically regulates the growth and survival of cancer cells. Dissecting the active molecules in tumor microenvironment may uncover the key factors that can impact cancer progression. Human NSCLC tumor tissue-conditioned medium (TCM) and adjacent nontumor tissue-conditioned medium (NCM) were used to treat two NSCLC cells LSC1 and LAC1, respectively. Cell growth and foci formation assays were applied to assess the effects of TCM and NCM on cancer cells. The active factors were identified by protein mass spectrometry. Cell growth and foci formation assays showed that 8 of 26 NCM and none of TCM could effectively lead to tumor cell lysis, which was known as tumoricidal activity. And then protein mass spectrometry analysis and functional verifications confirmed that complement component 9 (C9) played a crucial role in the complement-dependent cytotoxicity (CDC)-mediated tumoricidal activity in vitro. Furthermore, immunofluorescent staining revealed that C9 specifically expressed in most alveolar macrophages (AMs) in adjacent lung tissues and a small fraction of tumor-associated macrophages (TAMs) in NSCLC tissues. Most importantly, the percentage of C9-positive cells in AMs or TAMs was responsible for the tumoricidal activity of NCM and TCM. Herein, we found that high expression of C9 in TAMs was a significant independent prognostic factor (P = 0.029), and associated with beneficial overall survival (P = 0.012) and disease-free survival (P = 0.016) for patients with NSCLC. Finally, we unveiled that hypoxic tumor microenvironment could switch the phenotype of macrophages from M1 to M2 forms, accompanying with the downregulation of C9 in TAMs. Collectively, our findings elucidated a novel role of TAMs expressing C9 in the prognosis of NSCLC patients, which provided a promising strategy in the development of anticancer treatments based on the CDC-mediated tumoricidal activity.

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YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression.

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YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression.

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