Aberrant TIG1 methylation associated with its decreased expression and clinicopathological significance in hepatocellular carcinoma

Chen, Xihua; Wu, Weiping; Ding, Jian

doi:10.1007/s13277-013-1129-9

Cited by 7 publications

(6 citation statements)

References 19 publications

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“…RARRES1 is a commonly silenced hypermethylated locus in many cancer types including prostate cancer [25], hepatocellular carcinoma [37], and breast cancer [17]. Although generally described as a putative tumor suppressor gene, a recent report indicated a pro-tumorigenic role for RARRES1 in a rare form of breast cancer, inflammatory breast cancer [16].…”

Section: Discussionmentioning

confidence: 99%

Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1

et al. 2016

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Breast cancer subtyping, based on the expression of hormone receptors and other genes, can determine patient prognosis and potential options for targeted therapy. Among breast cancer subtypes, tumors of basal-like and claudin-low subtypes are typically associated with worse patient outcomes, are primarily classified as triple-negative breast cancers (TNBC), and cannot be treated with existing hormone-receptor-targeted therapies. Understanding the molecular basis of these subtypes will lead to the development of more effective treatment options for TNBC. In this study, we focus on retinoic acid receptor responder 1 (RARRES1) as a paradigm to determine if breast cancer subtype dictates protein function and gene expression regulation. Patient tumor dataset analysis and gene expression studies of a 26 cell-line panel, representing the five breast cancer subtypes, demonstrate that RARRES1 expression is greatest in basal-like TNBCs. Cell proliferation and tumor growth assays reveal that RARRES1 is a tumor suppressor in TNBC. Furthermore, gene expression studies, Illumina HumanMethylation450 arrays, and chromatin immunoprecipitation demonstrate that expression of RARRES1 is retained in basal-like breast cancers due to hypomethylation of the promoter. Additionally, expression of the cancer stem cell marker, aldehyde dehydrogenase 1A3, which provides the required ligand (retinoic acid) for RARRES1 transcription, is also specific to the basal-like subtype. We functionally demonstrate that the combination of promoter methylation and retinoic acid signaling dictates expression of tumor suppressor RARRES1 in a subtype-specific manner. These findings provide a precedent for a therapeutically-inducible tumor suppressor and suggest novel avenues of therapeutic intervention for patients with basal-like breast cancer.

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Section: Discussionmentioning

confidence: 99%

Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1

et al. 2016

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“…Aberrant methylation of RIG1 and inactive transcription were also found in gastric cancer cell lines and tissues [66,234], but also in the non-neoplastic gastric epithelia of elderly subjects and correlated with the risk to develop gastric cancer [235]. Abnormal methylation was also found in HCC tissues than in adjacent non-cancerous tissues [236], and correlated with carcinogenesis event of the liver and biliary tract [237]. A 2017 paper correlated the epigenetic silencing of RIG1 with the over-expression of the G9a histone methyl-transferase, up-regulated in HCC (Figure 3) RAI genes were first described by Imai and co-workers [239] as a retinoic-acid regulated genes from whence derived their names.…”

Section: Retinoid-inducible Gene 1 (Rig1) Hypermethylationmentioning

confidence: 91%

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

Costantini

Molinari

Farinon

et al. 2020

JCM

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Although the use of oral administration of pharmacological all-trans retinoic acid (ATRA) concentration in acute promyelocytic leukaemia (APL) patients was approved for over 20 years and used as standard therapy still to date, the same use in solid cancers is still controversial. In the present review the literature about the top five lethal solid cancers (lung, stomach, liver, breast, and colon cancer), as defined by The Global Cancer Observatory of World Health Organization, and retinoic acids (ATRA, 9-cis retinoic acid, and 13-cis retinoic acid, RA) was compared. The action of retinoic acids in inhibiting the cell proliferation was found in several cell pathways and compartments: from membrane and cytoplasmic signaling, to metabolic enzymes, to gene expression. However, in parallel in the most aggressive phenotypes several escape routes have evolved conferring retinoic acids-resistance. The comparison between different solid cancer types pointed out that for some cancer types several information are still lacking. Moreover, even though some pathways and escape routes are the same between the cancer types, sometimes they can differently respond to retinoic acid therapy, so that generalization cannot be made. Further studies on molecular pathways are needed to perform combinatorial trials that allow overcoming retinoic acids resistance.

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“…In contrast to its close relationship to fibrosis, RARRES1 is uncoupled from ARRB2 signaling in HCC. The downregulation of RARRES1 in HCC and other cancers is mediated by hypermethylation of RARRES1 (36,37), which seems to be independent of ARRB2. Since RARRES1 improves survival in HCC, inhibition of hypermethylation potentially halts HCC progression.…”

Section: Schierwagen Et Almentioning

confidence: 94%

Intercellular crosstalk regulating ARRB2/RARRES1 is involved in transition from fibrosis to cancer

Schierwagen

Dietrich

Heinzen

et al. 2021

Preprint

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Progressive fibrogenesis in chronic liver injury is often associated with cancer development. Beta-arrestin-2 (ARRB2) is a regulator of the profibrotic Angiotensin II type 1 receptor (AGTR1). The role of ARRB2 in liver fibrosis and in the transition from fibrosis to cancer is not fully understood and was investigated in this study. This study demonstrates that upregulation of the retinoic acid receptor responder 1 (RARRES1) in HSC mediated by ARRB2 leads to fibrosis. This process is driven by exosomal ARRB2 transfer to HSC, major fibrosis contributors, from injured hepatocytes, which highly express ARRB2. By contrast, downregulation of RARRES1 in hepatocytes induces malignant transformation and hepatocellular carcinoma (HCC) development. Consequently, Arrb2-deficient mice show higher number and size of liver tumors than wild-type mice in a hepatocellular carcinoma model with fibrosis. The identified relationship between ARRB2 and RARRES1 was observed in at least two species, including human cells and tissues in fibrosis and HCC and has a predictive value for survival in cancer patients. This study describes the discovery of a novel molecular pathway mediating the transition from fibrosis to cancer offering potential diagnostics and therapeutics.

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Aberrant TIG1 methylation associated with its decreased expression and clinicopathological significance in hepatocellular carcinoma

Cited by 7 publications

References 19 publications

Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1

Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

Intercellular crosstalk regulating ARRB2/RARRES1 is involved in transition from fibrosis to cancer

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