Theranostics 2020; 10(6):2553-2570. doi:10.7150/thno.41120

Research Paper

HIF-1ɑ-regulated miR-1275 maintains stem cell-like phenotypes and promotes the progression of LUAD by simultaneously activating Wnt/β-catenin and Notch signaling

Neng Jiang1, Chang Zou2, Ying Zhu3, Yifeng Luo4, Lili Chen1, Yiyan Lei5, Kejing Tang4, Yu Sun1, Wenhui Zhang1, Shuhua Li1, Qiong He1, Jianwen Zhou1, Yangshan Chen1, Jiping Luo1, Wenting Jiang1, Zunfu Ke1✉

1. Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
2. Clinical Medical Research Center, The First Affiliated Hospital of Southern University, the Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong, China
3. Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
4. Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
5. Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

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Citation:
Jiang N, Zou C, Zhu Y, Luo Y, Chen L, Lei Y, Tang K, Sun Y, Zhang W, Li S, He Q, Zhou J, Chen Y, Luo J, Jiang W, Ke Z. HIF-1ɑ-regulated miR-1275 maintains stem cell-like phenotypes and promotes the progression of LUAD by simultaneously activating Wnt/β-catenin and Notch signaling. Theranostics 2020; 10(6):2553-2570. doi:10.7150/thno.41120. Available from http://www.thno.org/v10p2553.htm

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Abstract

Rationale: Cancer stem cells (CSCs) are considered to be essential for tumorigenesis, recurrence, and metastasis and therefore serve as a biomarker for tumor progression in diverse cancers. Recent studies have illustrated that specific miRNAs exhibit novel therapeutic potential by controlling CSC properties. miR-1275 is upregulated in lung adenocarcinoma (LUAD) and enhances its stemness. However, the underlying mechanisms have not been elucidated.

Methods: miRNA expression microarray of LUAD and adjacent nontumor tissues was used to identify miRNAs involved in LUAD malignant progression. miR-1275 expression level was determined using quantitative real-time PCR (RT-qPCR) and in situ hybridization (ISH), and its correlation with clinicopathological characteristics was analyzed in LUAD specimens. The upstream regulator of miR-1275 was validated by chromatin immunoprecipitation (ChIP). The biological functions and underlying mechanisms of miR-1275 were investigated both in vitro and in vivo.

Results: MiR-1275 was highly upregulated in lung cancer cell lines and LUAD tissues. Overexpression of miR-1275 in lung cancer patients was associated with shorter overall- and recurrence-free-survival. Proto-oncogene HIF-1ɑ was identified as the transcription mediator of miR-1275. Activation of Wnt/β-catenin and Notch signaling by miR-1275 was found to enhance the stemness of LUAD cells, while antagonizing miR-1275 or suppressing Wnt/β-catenin and Notch pathways potently reversed miR-1275-induced pathway co-activation and stemness. Enhanced stemness dramatically promoted tumorigenicity, recurrence, and metastasis. miR-1275 directly targeted multiple antagonists of Wnt/β-catenin and Notch pathways, including DKK3, SFRP1, GSK3β, RUNX3, and NUMB, respectively, which resulted in signaling activation.

Conclusions: Our findings identified miR-1275 as a potential oncogene in LUAD that exerts its tumorigenic effect through co-activating Wnt/β-catenin and Notch signaling pathways. Thus, HIF-1ɑ-regulated miR-1275 might be a potential therapeutic target for LUAD.

Keywords: MiR-1275, LUAD, Stemness, Wnt/β-catenin, Notch