Mutual regulation of HIF-1α and circ-UBE2G1 under hypoxic microenvironment promotes thyroid cancer metastasis

DENG Xiaoling; ZHANG Nengying; LONG Kaiguo; ZENG Feng

doi:10.16016/j.2097-0927.202504040

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Mutual regulation of HIF-1α and circ-UBE2G1 under hypoxic microenvironment promotes thyroid cancer metastasis

Basic Medicine | 更新时间：2025-07-25

- Mutual regulation of HIF-1α and circ-UBE2G1 under hypoxic microenvironment promotes thyroid cancer metastasis
- Journal of Army Medical University Vol. 47, Issue 14, Pages: 1612-1622(2025)
- 作者机构：
  
  遵义医科大学第二附属医院甲乳外科，贵州遵义
- 作者简介：
  
  ZENG Feng， E-mail： tong13639146162@163.com
- 基金信息：
  
  the Science and Technology Fund of Guizhou Provincial Health Commission(gzwkj2022-345)
- DOI：10.16016/j.2097-0927.202504040
  CLC： R394.3;R73-37;R736.1
- Received：10 April 2025，
  
  Revised：21 June 2025，
  
  Published：30 July 2025
- 稿件说明：
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邓小玲，张能英，龙开国，等.缺氧微环境下HIF-1α与circ-UBE2G1相互调控促进甲状腺癌转移［J］.陆军军医大学学报，2025，47（14）：1612-1622.DOI：10.16016/j.2097-0927.202504040.

DENG X L，ZHANG N Y，LONG K G，et al.Mutual regulation of HIF-1α and circ-UBE2G1 under hypoxic microenvironment promotes thyroid cancer metastasis［J］.J Army Med Univ，2025，47（14）：1612-1622.DOI：10.16016/j.2097-0927.202504040.
邓小玲，张能英，龙开国，等.缺氧微环境下HIF-1α与circ-UBE2G1相互调控促进甲状腺癌转移［J］.陆军军医大学学报，2025，47（14）：1612-1622.DOI：10.16016/j.2097-0927.202504040. DOI：

DENG X L，ZHANG N Y，LONG K G，et al.Mutual regulation of HIF-1α and circ-UBE2G1 under hypoxic microenvironment promotes thyroid cancer metastasis［J］.J Army Med Univ，2025，47（14）：1612-1622.DOI：10.16016/j.2097-0927.202504040. DOI：

摘要

目的

探究缺氧微环境下缺氧诱导因子（hypoxia-inducible factor，HIF）-1α与circ-UBE2G1相互调控促进甲状腺癌（thyroid cancer，THCA）转移的机制。

方法

利用GEPIA数据库分析circ-UBE2G1与HIF-1α在THCA中的表达特点及相关性，通过Kaplan-Meier生存曲线分析circ-UBE2G1和miR-330-3p与生存率的关系。THCA细胞暴露于缺氧环境，通过转染沉默HIF-1α分析HIF-1α对circ-UBE2G1转录的调控，并通过转染来沉默circ-UBE2G1。通过靶序列预测和双荧光素酶报告基因验证miR-330-3p与circ-UBE2G1或HIF-1α的靶向关系。利用转染分析HIF-1α过表达以及circ-UBE2G1沉默对THCA细胞迁移和侵袭的影响。通过皮下注射HIF-1α过表达以及circ-UBE2G1沉默的THCA细胞构建荷瘤裸鼠模型。临床收集THCA组织和癌旁正常样本分析circ-UBE2G1、miR-330-3p与HIF-1α的表达及相关性。

结果

生信分析结果表明circ-UBE2G1与HIF-1α呈正相关（

0.01），circ-UBE2G1的高表达与THCA患者低生存率相关（

=0.024）。抑制HIF-1α阻断缺氧对circ-UBE2G1的促进作用（

0.05）。沉默circ-UBE2G1抑制THCA细胞迁移和侵袭，逆转HIF-1α对其的促进作用（

0.05）。双荧光素酶报告基因显示，miR-330-3p分别与circ-UBE2G1和HIF-1α靶向结合（

0.05）。沉默circ-UBE2G1导致miR-330-3p水平升高（

0.05），而增加miR-330-3p则抑制HIF-1α的表达（

0.05）。临床THCA样本中circ-UBE2G1与HIF-1α均升高且呈正相关（

0.05），并且THCA样本中miR-330-3p低表达且分别与circ-UBE2G1和HIF-1α呈负相关（

0.05）。

结论

缺氧通过诱导HIF-1α表达促进circ-UBE2G1的转录，circ-UBE2G1通过靶向miR-330-3p促进HIF-1α的表达，从而促进THCA转移。

Abstract

Objective To investigate the mechanism by which hypoxia-inducible factor (HIF)-1α and circ-UBE2G1 mutually regulate and promote thyroid cancer (THCA) metastasis under hypoxic microenvironment. ‍Methods The GEPIA database was used to analyze the expression characteristics and correlation between ci

rc-UBE2G1 and HIF-1α in THCA. The relationship of circ-UBE2G1 and miR-330-3p with survival rate was analyzed using Kaplan-Meier survival curve. After THCA cells were exposed to hypoxia

HIF-1α was silenced by transfection to analyze its regulation for circ-UBE2G1 transcription. The targeting relationship between miR-330-3p and either circ-UBE2G1 or HIF-1α was verified by sequence prediction and dual luciferase reporter assay. The effects of HIF-1α overexpression and circ-UBE2G1 silencing on THCA cell migration and invasion were analyzed after corresponding transfections. A tumor-bearing nude mouse model was established by subcutaneous injection of THCA cells with HIF-1α overexpression and circ-UBE2G1 silencing

respectively. THCA tissues and adjacent normal samples were clinically collected to analyze the expression levels and correlations of circ-UBE2G1

miR-330-3p

and HIF-1α. Results‍　‍Bioinformatics analysis showed that circ-UBE2G1 was positively correlated with HIF-1α (

0.01)

and its high expression was associated with a low survival rate in THCA patients (

=0.024). Inhibition of HIF-1α blocked the promotive effect of hypoxia on circ-UBE2G1 (

0.05). Silencing circ-UBE2G1 inhibited the migration and invasion of THCA cells (

0.05)

and reversed the promotive effect of HIF-1α on these processes (

0.05). Dual luciferase reporter gene assay revealed that miR-330-3p targeted both circ-UBE2G1 and HIF-1α (

0.05). Silencing circ-UBE2G1 led to increased levels of miR-330-3p (

0.05)

whereas increasing miR-330-3p inhibited the expression of HIF-1α (

0.05). In clinical THCA samples

both circ-UBE2G1 and HIF-1α were increased and positively correlated (

0.05)

while miR-330-3p was lowly expressed and negatively correlated with both circ-UBE2G1 and HIF-1α (

0.05). Conclusion‍　‍Hypoxia promotes the transcription of circ

-UBE2G1 by inducing HIF-1α expression

and circ-UBE2G1 promotes HIF-1α expression by targeting miR-330-3p

thereby promoting THCA metastasis.

关键词

Keywords

references

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