Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Oct 15, 2022; 14(10): 1918-1932
Published online Oct 15, 2022. doi: 10.4251/wjgo.v14.i10.1918
Transcriptional factor III A promotes colorectal cancer progression by upregulating cystatin A
Jing Wang, Yuan Tan, Qun-Ying Jia, Fa-Qin Tang
Jing Wang, Yuan Tan, Qun-Ying Jia, Fa-Qin Tang, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
Author contributions: Tang FQ designed and coordinated the study; Wang J, Tan Y, and Jia QY performed the experiments, and acquired and analyzed data; Wang J and Tang FQ wrote the manuscript; and all authors approved the final version of the article.
Supported by the National Natural Science Foundation of China, No. 81872226; Changsha Science and Technology Project, No. 2019TP1046; and the Research Projects of Hunan Health Commission, No. B2019084.
Institutional review board statement: The study was reviewed and approved by the Hunan Cancer Hospital Institutional Review Board (Approval No. KYJJ-2020-004).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Hunan Cancer Hospital (No. 2020-118).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Fa-Qin Tang, MD, PhD, Doctor, Professor, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, No. 283 Tongzipo Road, Changsha 410013, Hunan Province, China. tangfq@hnca.org.cn
Received: May 7, 2022
Peer-review started: May 7, 2022
First decision: July 13, 2022
Revised: July 23, 2022
Accepted: September 8, 2022
Article in press: September 8, 2022
Published online: October 15, 2022
Processing time: 160 Days and 9.1 Hours
Abstract
BACKGROUND

Advanced colorectal cancer (CRC) generally has poor outcomes and high mortality rates. Clarifying the molecular mechanisms underlying CRC progression is necessary to develop new diagnostic and therapeutic strategies to improve CRC outcome and decrease mortality. Transcriptional factor III A (GTF3A), an RNA polymerase III transcriptional factor, is a critical driver of tumorgenesis and aggravates CRC cell growth.

AIM

To confirm whether GTF3A promotes CRC progression by regulating the expression of cystatin A (Csta) gene and investigate whether GTF3A can serve as a prognostic biomarker and therapeutic target for patients with CRC.

METHODS

Human tissue microarrays containing 90 pairs of CRC tissues and adjacent non-tumor tissues, and human tissue microarrays containing 20 pairs of CRC tissues, adjacent non-tumor tissues, and metastatic tissues were examined for GTF3A expression using immunohistochemistry. The survival rates of patients were analyzed. Short hairpin GTF3As and CSTAs were designed and packaged into the virus to block the expression of Gtf3a and Csta genes, respectively. In vivo tumor growth assays were performed to confirm whether GTF3A promotes CRC cell proliferation in vivo. Electrophoretic mobility shift assay and fluorescence in situ hybridization assay were used to detect the interaction of GTF3A with Csta, whereas luciferase activity assay was used to evaluate the expression of the Gtf3a and Csta genes. RNA-Sequencing (RNA-Seq) and data analyses were used to screen for target genes of GTF3A.

RESULTS

The expression of GTF3A was higher in CRC tissues and lymph node metastatic tissues than in the adjacent normal tissues. GTF3A was associated with CRC prognosis, and knockdown of the Gtf3a gene impaired CRC cell proliferation, invasion, and motility in vitro and in vivo. Moreover, RNA-Seq analysis revealed that GTF3A might upregulate the expression of Csta, whereas the luciferase activity assay showed that GTF3A bound to the promoter of Csta gene and increased Csta transcription. Furthermore, CSTA regulated the expression of epithelial-mesenchymal transition (EMT) markers.

CONCLUSION

GTF3A increases CSTA expression by binding to the Csta promoter, and increased CSTA level promotes CRC progression by regulating the EMT. Inhibition of GTF3A prevents CRC progression. Therefore, GTF3A is a potential novel therapeutic target and biomarker for CRC.

Keywords: Transcription factor IIIA; Cystatin A; Colorectal cancer; Epithelial-mesenchymal transition

Core Tip: Transcriptional factor III A (GTF3A) is highly expressed in colorectal cancer (CRC) tissues, and GTF3A expression is associated with CRC prognosis. GTF3A binds to the promoter of cystatin (Csta) gene to facilitate Csta transcription, which regulates the expression of epithelial-mesenchymal transition markers and promotes CRC progression. Blocking GTF3A significantly inhibits CRC cell growth. Therefore, GTF3A is a potential novel therapeutic target and prognostic biomarker for CRC.