The New Role of HNF1A-NAS1/miR-214/INHBA Signaling Axis in Colorectal Cancer

¹ Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, 650118 Kunming, Yunnan, China

² Department of Head and Neck Tumor Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, 650118 Kunming, Yunnan, China

³ Laboratory of Molecular Diagnosis Center, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, 650118 Kunming, Yunnan, China

⁴ Department of Hospital Affairs, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, 650118 Kunming, Yunnan, China

⁵ Department of Oncology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, 650118 Kunming, Yunnan, China

⁶ Department of Minimally Invasive Intervention, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, 650118 Kunming, Yunnan, China

^*Correspondence: dingrong2@kmmu.edu.cn (Rong Ding); liyunfeng@kmmu.edu.cn (Yunfeng Li)
^†These authors contributed equally.

Front. Biosci. (Landmark Ed) 2023, 28(11), 301; https://doi.org/10.31083/j.fbl2811301

Submitted: 30 December 2022 | Revised: 9 April 2023 | Accepted: 17 April 2023 | Published: 24 November 2023

(This article belongs to the Special Issue Recent Advances in Cancer Research and Environmental Toxicology)

This is an open access article under the CC BY 4.0 license.

Abstract

Background: Colorectal cancer (CRC) is the third most common cancer and one of the leading causes of death worldwide. Seriously threatens human life and health. Previous studies have identified that inhibin $\beta{}$ A (INHBA) could induce tumorgenesis and progression of CRC through the regulation of the TGF- $\beta{}$ /Smad signal axis. The abnormal expression of INHBA is related to the poor prognosis of patients. The aim of this study was to identify the molecular mechanism of HNF1A-AS1 and miR-214 regulating INHBA and carcinogenesis through bioinformatics combined with experiments. Methods: The expression of HNF1A-AS1, miRNA-214-5p, INHBA in pan-cancer and CRC were investigated in the Cancer Genome Atlas (TCGA). The correlation between HNF1A-AS1 and immune-related genes or miRNAs was explored via the Gene Expression Profiling Interactive Analysis (GEPIA) and volcano plots, respectively. The association between HNF1A-AS1 and differentially expressed miRNAs was constructed by TargetScan. The miRDB, miRWalk, and TargetScan databases were utilized to predict the target genes of hsa-miR-214. The expression of INHBA in tissues and cell lines of CRC was examined by RT-qPCR and western blot assay. Results: The INHBA and HNF1A-AS1 expressions were increased in Colon adenocarcinoma (COAD) and Rectum adenocarcinoma (READ) of the TCGA database. Hsa-miR-214 was relatively less expressed in CRC tissues compared with para-cancer tissues. The expression of HNF1A-AS1 was negatively correlated with hsa-miR-214. INHBA was one of the target genes of hsa-miR-214 based on miRDB, miRWalk, and TargetScan databases. The specific binding sites of INHBA-3’UTR and miR-214-5p were identified by starBase. The expression level of INHBA was positively correlated with the T stage of tumor and negatively correlated with overall survival (OS) and disease-free survival (DFS) in CRC patients. The results of RT-qPCR and western blot indicated that the expression of INHBA in tissues and cell lines in CRC was higher than those in para-carcinoma tissues and normal colon cell lines, respectively. Conclusions: These findings suggested that HNF1A-AS1 and miRNA-214-5p were key upstream non-coding RNAs of INHBA. The HNF1A-AS1/miR-214/INHBA signal axis plays a significant role in the tumorgenesis and progression of CRC. By interfering with HNF1A-AS1 and INHBA genes on HT29 and SW480 cells, it was found that HNF1A-AS1 and INHBA genes may be important target genes in CRC.

Keywords

colorectal cancer

HNF1A-AS1

miR-214

INHBA

TGF-β/Smad

Funding

82060542/National Natural Science Foundation of China

2022J0227/Scientific Research Fund of Yunnan Provincial Education Department

202201AY070001-14/Joint Special Funds for the Department of Science and Technology of Yunnan Province-Kunming Medical University

2022B13/Innovation Fund for Doctoral Students of Kunming Medical University

Figures

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Fig. 1.

LncRNA HNF1A-AS1 is up-regulated and associated with OS. (A,B) The expression of HNF1A-AS1 in disparate types of cancers were exhibited with red dots and in para-cancer is shown with green dots. Data derived from TCGA database portal in GEPIA. (B) The horizontal axis shows the type of tumor and the height of the bar represents the median expression of certain tumor types or normal tissue. (C) Kaplan-Meier analysis of colon cancer patients with high (n = 134) or low (n = 135) HNF1A-AS1 levels. Statistical analysis was performed by log-rank test. (D) Kaplan-Meier analysis of rectal cancer patients with high (n = 45) or low (n = 45) HNF1A-AS1 levels. Statistical analysis was performed by log-rank test. (E) The expression of HNF1A-AS1 is up-regulated in colon cancer compared with para-cancer tissues (*p $<$ 0.05). (F) The expression of HNF1A-AS1 is up-regulated in rectal cancer compared with the para-cancer tissues (*p $<$ 0.05). The triangle symbol highlights the two genes. The triangle symbol highlights the two tumor; OS,overall survival; COAD, colon adenocarcinoma; READ, rectum adenocarcinoma; HNF1A-AS1, LncRNA HNF1A antisense RNA 1.

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