The role of hepatocyte nuclear factor 4α (HNF4α) in tumorigenesis

Sang, Lei; Wang, Xingshun; Bai, Weiyu; Shen, Junling; Zeng, Yong; Sun, Jun

doi:10.3389/fonc.2022.1011230

Cited by 8 publications

(5 citation statements)

References 63 publications

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“…Previous studies have shown that HNF4α could behave as either a tumor suppressor or an oncogene largely depending on the tumor type and organ[10, 18, 19]. Thus, we next investigated the function of HNF4α in CRC by stable transfection of HNF4α into SW480 and SW620 colon cancer cell lines.…”

Section: Resultsmentioning

confidence: 99%

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HNF4α is a target of the Wnt/β-catenin pathway and regulates colorectal carcinogenesis

Sang,

Bai,

et al. 2024

Preprint

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Hepatocyte nuclear factor 4alpha (HNFalpha) is a transcription factor involved in liver function. Dysregulation of HNF4alpha leads to hepatocarcinogenesis. However, the role and mechanism of HNF4alpha; in colorectal cancer is still unknown. Here we demonstrate that HNF4alpha is upregulated in colorectal cancers. and HNF4alpha upregulation promotes colorectal tumorigenesis. Notably, expression levels of HNF4alpha are positively correlated with the Wnt/beta-catenin signaling pathway in colorectal cancer patients. Further, we showed that HNF4alpha is transcriptionally activated by Wnt/beta-catenin/TCF3 and is at least partially responsible for the oncognesis activity of the Wnt signaling in colorectal cancer. Our findings indicate that HNF4alpha is a direct target of that Wnt/beta-catenin pathway and could play an important role in colorectal carcinogenesis.

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Section: Resultsmentioning

confidence: 99%

“…Recently, we found that the loss of nhr-14 gene in c. elegans resulted in the dysregulation of DNA damage-induced response [14], which usually leads to cancer development [15][16][17][18]. Thus, we examined HNF4α expression levels in different cancers and matched paired normal tissues.…”

Section: Hnf4 α Promotes Colorectal Carcinogenesismentioning

confidence: 99%

HNF4α is a target of the Wnt/β-catenin pathway and regulates colorectal carcinogenesis

Sang,

Bai,

et al. 2024

Preprint

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“…Some visualized figures are generated in real time to allow investigation of the cancer-type specificity and potential targets of enriched TFs (Figure 2E ). For instance, HNF4A, a well-established gastrointestinal-specific transcription factor ( 54 ), ranked as the second most enriched TF in colorectal cancer-specific CREs (Figure 2D ). HNF4A exhibited the highest expression levels in both colorectal cancer tissues and cell lines, regulated many target genes and was essential for the viability of the majority of colorectal cancer cells in the unbiased high-throughput CRISPR screening (Figure 2E ).…”

Section: Resultsmentioning

confidence: 99%

TSCRE: a comprehensive database for tumor-specific cis-regulatory elements

Peng,

Liu,

Zheng

et al. 2024

NAR Cancer

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Cis-regulatory elements (CREs) and super cis-regulatory elements (SCREs) are non-coding DNA regions which influence the transcription of nearby genes and play critical roles in development. Dysregulated CRE and SCRE activities have been reported to alter the expression of oncogenes and tumor suppressors, thereby regulating cancer hallmarks. To address the strong need for a comprehensive catalogue of dysregulated CREs and SCREs in human cancers, we present TSCRE (http://tscre.zsqylab.com/), an open resource providing tumor-specific and cell type-specific CREs and SCREs derived from the re-analysis of publicly available histone modification profiles. Currently, TSCRE contains 1 864 941 dysregulated CREs and 68 253 dysregulated SCREs identified from 1366 human patient samples spanning 17 different cancer types and 9 histone marks. Over 95% of these elements have been validated in public resources. TSCRE offers comprehensive annotations for each element, including associated genes, expression patterns, clinical prognosis, somatic mutations, transcript factor binding sites, cancer-type specificity, and drug response. Additionally, TSCRE integrates pathway and transcript factor enrichment analyses for each study, enabling in-depth functional and mechanistic investigations. Furthermore, TSCRE provides an interactive interface for users to explore any CRE and SCRE of interest. We believe TSCRE will be a highly valuable platform for the community to discover candidate cancer biomarkers.

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“…The transcription of NTCP and cytochromes P450 (CYPs) is reported to be regulated by hepatocyte nuclear factors (HNFs) [ 34 , 35 , 36 ]. Particularly, HNF1α and HNF4α are highly expressed in CRC tumors, the former is linked with tumor malignancy of CRC cells and the latter is considered as a critical risk factor for CRC [ 37 , 38 , 39 ]. HNF4α is known to be a direct trans-activator of NTCP and CYPs [ 34 , 35 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

A High Hepatic Uptake of Conjugated Bile Acids Promotes Colorectal Cancer—Associated Liver Metastasis

Zheng

Wei

Hou

et al. 2022

Cells

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The liver is the most common site for colorectal cancer (CRC)–associated metastasis. There remain unsatisfactory medications in liver metastasis given the incomplete understanding of pathogenic mechanisms. Herein, with an orthotopic implantation model fed either regular or high-fat diets (HFD), more liver metastases were associated with an expansion of conjugated bile acids (BAs), particularly taurocholic acid (TCA) in the liver, and an increased gene expression of Na+–taurocholate cotransporting polypeptide (NTCP). Such hepatic BA change was more apparently shown in the HFD group. In the same model, TCA was proven to promote liver metastases and induce a tumor-favorable microenvironment in the liver, characterizing a high level of fibroblast activation and increased proportions of myeloid-derived immune cells. Hepatic stellate cells, a liver-residing source of fibroblasts, were dose-dependently activated by TCA, and their conditioned medium significantly enhanced the migration capability of CRC cells. Blocking hepatic BA uptake with NTCP neutralized antibody can effectively repress TCA–triggered liver metastases, with an evident suppression of tumor microenvironment niche formation. This study points to a new BA–driven mechanism of CRC–associated liver metastases, suggesting that a reduction of TCA overexposure by limiting liver uptake is a potential therapeutic option for CRC—associated liver metastasis.

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The role of hepatocyte nuclear factor 4α (HNF4α) in tumorigenesis

Cited by 8 publications

References 63 publications

HNF4α is a target of the Wnt/β-catenin pathway and regulates colorectal carcinogenesis

HNF4α is a target of the Wnt/β-catenin pathway and regulates colorectal carcinogenesis

TSCRE: a comprehensive database for tumor-specific cis-regulatory elements

A High Hepatic Uptake of Conjugated Bile Acids Promotes Colorectal Cancer—Associated Liver Metastasis

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