Theranostics 2019; 9(16):4795-4810. doi:10.7150/thno.30988 This issue

Research Paper

Hypoxia-induced feedback of HIF-1α and lncRNA-CF129 contributes to pancreatic cancer progression through stabilization of p53 protein

Mingliang Liu1*, Jianxin Zhong1*, Zhu Zeng1*, Kang Huang1*, Zeng Ye2, Shijiang Deng2, Hengyu Chen1, Fengyu Xu1, Qiang Li2, Gang Zhao1✉

1. Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
2. Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
*These authors contributed equally to this work.

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Citation:
Liu M, Zhong J, Zeng Z, Huang K, Ye Z, Deng S, Chen H, Xu F, Li Q, Zhao G. Hypoxia-induced feedback of HIF-1α and lncRNA-CF129 contributes to pancreatic cancer progression through stabilization of p53 protein. Theranostics 2019; 9(16):4795-4810. doi:10.7150/thno.30988. Available from https://www.thno.org/v09p4795.htm

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Abstract

Graphic abstract

Rationale: Emerging evidences have highlighted the critical roles of lncRNAs in human cancer development. The work sought to assess the biological role and potential underlying mechanisms of lncRNA-CF129 (CF129) which is significantly reduced in pancreatic cancer (PC).

Methods: CF129 expression and its association with multiple clinicopathologic characteristics in PC specimens were analyzed. The role of CF129 both in vitro and in vivo was assessed, with RNA pull-down and immunoprecipitation assays being performed to detect the interaction between CF129 and p53 and E3 ligase MKRN1. Chromatin immunoprecipitation and luciferase assays were utilized to identify the interaction between p53 and FOXC2 promoter, HIF-1α/HDAC1 complex and CF129 promoter, FOXC2 and HIF-1α promoter, respectively.

Results: CF129 levels were markedly lower in PC compared with paired non-tumor adjacent tissues. Low CF129 expression predicted short overall survival in PC patients. CF129 inhibited invasion and metastasis of PC cells in a FOXC2-dependent manner. In addition, CF129 regulates FOXC2 transcription through association with mutant p53. CF129 directly binds to p53 and E3 ligase MKRN1, and such an interaction leading to p53 protein ubiquitination and degradation. Furthermore, CF129 is a hypoxia-responsive lncRNA, which is transcriptionally downregulated by binding between HIF-1α/HDAC1 complex and CF129 promoter. Finally, it is revealed that HIF-1α is reciprocally regulated by FOXC2 in transcriptional level. Clinically, CF129 downregulation coordinates overexpression of FOXC2.

Conclusions: Our study suggests that CF129 inhibits pancreatic cell proliferation and invasion by suppression of FOXC2 transcription, which depends on MKRN1-mediated ubiquitin-dependent p53 degradation. The HIF-1α/CF129/ p53/FOXC2 axis may function as a potential biomarker and therapeutic target.

Keywords: pancreatic cancer, lncRNA, HIF-1α, p53, MKRN1, FOXC2