ZC3H12A inhibits tumor growth and metastasis of breast cancer under hypoxic condition via the inactivation of IL-17 signaling pathway

ABSTRACT

Hypoxia is a major contributor to tumor microenvironment (TME) and metastasis in most solid tumors. We seek to screen hypoxia-related genes affecting metastasis in breast cancer and to reveal relative potential regulatory pathway. Based on gene expression profiling of GSE17188 dataset, differential expressed genes (DEGs) were identified between highly metastatic breast cancer cells under hypoxia and samples under normoxia. The protein–protein interaction (PPI) network was utilized to determine hub genes. The gene expression profiling interactive analysis database (GEPIA2) and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were employed to quantify hub genes. Moreover, overexpression of zinc finger CCCH-type containing 12A (ZC3H12A) was performed both in breast cancer cells and xenograft mouse model to determine the role of ZC3H12A. We identified 134 DEGs between hypoxic and normoxic samples. Based on PPI analysis, 5 hub genes interleukin (IL)-6, GALN (GAL), CD22 molecule (CD22), ZC3H12A and TNF receptor associated factor 1 (TRAF1) were determined; the expression levels of TRAF1, IL-6, ZC3H12A and GAL were remarkably downregulated while CD22 was upregulated in breast cancer cells. Besides, patients with higher expression of ZC3H12A had favorable prognosis. Overexpression of ZC3H12A could inhibit metastasis and tumor growth of breast cancer; overexpression of ZC3H12A downregulated the expression of IL-17 signaling pathway-related proteins such as IL-17 receptor A (IL-17RA), IL-17A and nuclear factor κB activator 1 (Act1). This study reveals ZC3H12A and IL-17 signaling pathway as potential therapeutic targets for hypoxic breast cancer.

KEYWORDS:

• Breast cancer
• hypoxia
• zinc finger CCCH-type containing 12A
• interleukin-17 signaling pathway

Authors’ contributions

Zhongbing Luo: Substantial contributions to conception and design, data acquisition, drafting the article;

Fulan Yang and Kang Liu: data acquisition, drafting the article;

Zhenluo Ding: data acquisition; reviewing the article;

All the authors took part in the experiment.

All the authors read and approved the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Availability of data and material

All data in the manuscript is available through the responsible corresponding author.

Ethical approval and consent to participate

The animal experiments conformed to the Guide for the Care and Use of Laboratory Animals. Animal study has been approved by the Animal Ethics Committee of Ganzhou People’s Hospital.

All experiments were performed in accordance with relevant guidelines and regulations.

The manuscript reporting adheres to the ARRIVE guidelines for the reporting of animal experiments.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15384101.2024.2314441

Additional information

Funding

The authors reported there is no funding associated with the work featured in this article.