The Oncogenic Role of TNFRSF12A in Colorectal Cancer and Pan-Cancer Bioinformatics Analysis

Sep 21, 2026

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Cancer is a major public health concern, making the identification of new cancer markers and therapeutic targets critically important. Elevated expression of tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) has been reported in multiple cancers. This study integrates bioinformatics analyses and experimental validation to define TNFRSF12A’s tumor-promoting functions. TNFRSF12A upregulation correlates with poor prognosis, and functional assays show that knockdown suppresses colorectal cancer progression while overexpression enhances malignancy in vitro and in vivo. Mechanistically, TNFRSF12A activates NF-κB signaling, inducing RELA-dependent BIRC3, supporting a TNFRSF12A/RELA/BIRC3 regulatory axis.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Purpose

Materials and Methods

Results

Conclusion

pISSN 1598-2998, eISSN 2005-9256 | [https://doi.org/10.4143/crt.2024.408](https://doi.org/10.4143/crt.2024.408) Cancer Res Treat. 2025;57(1):212-228

Original Article
The Oncogenic Role ofTNFRSF12A in Colorectal Cancer and Pan-Cancer Bioinformatics Analysis
Chuyue Wang1,2,3,4 , Yingying Zhao1,2,3,4 , You Chen1,2,3,4 , Ying Shi1,2,3,4 , Zhiying Yang1,2,3,4 , Weili Wu1,2,3,4 , Rui Ma5 , Bo Wang5 , Yifeng Sun6 , Ping Yuan1,2,3,4
1Guangdong Institute of Gastroenterology, Guangzhou, 2Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 3Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 4Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 5Department of Medical Oncology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 6Sing Loong Limited, Hong Kong Special Administrative Region, China | | | --- | --- | | Purpose Cancer has become a significant major public health concern, making the discovery of new cancer markers or therapeutic targets exceptionally important. Elevated expression of tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) expression has been observed in certain types of cancer. This project aims to investigate the function of TNFRSF12A in tumors and the underlying mechanisms.
Materials and Methods Various websites were utilized for conducting the bioinformatics analysis. Tumor cell lines with stable knockdown or overexpression ofTNFRSF12A were established for cell phenotyping experiments and subcutaneous tumorigenesis in BALB/c mice. RNA-seq was employed to investigate the mechanism of TNFRSF12A.
Results TNFRSF12A was upregulated in the majority of cancers and associated with a poor prognosis. Knockdown TNFRSF12A hindered the colorectal cancer progression, while overexpression facilitated malignancy both in vitro and in vivo. TNFRSF12A overexpression led to increased nuclear factor кB (NF-κB) signaling and significant upregulation of baculoviral IAP repeat containing 3 (BIRC3), a transcription target of the NF-κB member RELA, and it was experimentally confirmed to be a critical downstream factor of TNFRSF12A. Therefore, we speculated the existence of a TNFRSF12A/RELA/BIRC3 regulatory axis in colorectal cancer.
Conclusion TNFRSF12A is upregulated in various cancer types and associated with a poor prognosis. In colorectal cancer, elevated TNFRSF12A expression promotes tumor growth, potentially through the TNFRSF12A/RELA/BIRC3 regulatory axis.
Key words TNFRSF12A, Computational biology, Neoplasms, Colorectal neoplasms, NF-κB | | | Introduction | Protein Atlas (HPA) [5], along with their derived secondary analysis websites, have significantly enhanced global cancer | | Cancer has become a major public health issue, with the | research effort. | | National Cancer Center of China (NCC) reporting approxi- | Tumor necrosis factor receptor superfamily member 12A | | mately 4,824,700 new cancer cases and 2,574,200 new can- | (TNFRSF12A), also known as Fn14, belongs to the tumor | | cer-related deaths in China in 2022 [1] . Moreover, the Inter- | necrosis factor (TNF) receptor superfamily. The intracellu- | | national Agency for Research on Cancer (IARC) estimates a global cancer burden of 28.4 million cases by 2040 [2] . In | lar segment of TNFRSF12A contains a TRAF-binding motif. When its extracellular cysteine-rich domain binds to the | | China, colorectal cancer ranks second in new cancer cases | trimeric form of a unique ligand TNFRSF12, also known as | | and fourth in cancer-related deaths in 2022 [1] . | TWEAK [6], TNFRSF12A becomes trimerized and activated. | | Even though there are established and effective treatment | This activation sets off downstream signaling via TRAF. It | | for various types of cancer, patients still face issues related | is also suggested that when TNFRSF12

FAQs

What is the study’s main objective regarding TNFRSF12A?

To investigate TNFRSF12A’s function in tumors and the underlying mechanisms. The study focuses on how TNFRSF12A contributes to cancer progression, particularly in colorectal cancer.

How were bioinformatics and experiments used in this research?

Various websites were used for bioinformatics analysis. Stable TNFRSF12A knockdown or overexpression models were tested with cell phenotype assays and subcutaneous tumorigenesis in BALB/c mice, and RNA-seq was used to examine the mechanism.

What mechanism links TNFRSF12A to colorectal cancer progression?

TNFRSF12A overexpression increases NF-κB signaling and significantly upregulates BIRC3, which is transcriptionally regulated by RELA. The results support a TNFRSF12A/RELA/BIRC3 regulatory axis in colorectal cancer.

Sep 21, 2026

Uploaded by Aurelia