Capicua suppresses hepatocellular carcinoma progression by controlling the ETV4–MMP1 axis

Kim, Eun-Jeong; Kim, Donghyo; Lee, Jeon-Soo; Yoe, Jeehyun; Park, Jong-Min; Kim, Chang‐Jin; Jeong, Dongjun; Kim, Sanguk; Lee, Yoontae

doi:10.1002/hep.29738

Cited by 75 publications

(92 citation statements)

References 51 publications

(130 reference statements)

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“…To examine the detailed mechanisms underlying M2 macrophages' role in regulating HCC cells invasion and migration, we tested the expression of proteins that have been connected with cancer cell invasion and migration [12][13][14][15][16][17][18] in both culture alone and in co-culture. The exploratory experiments led to the focus on MMP9 as the results showed that MMP9 protein expression was increased after co-culture, both in SK-HEP-1 and HA22T HCC cells ( Fig.…”

Section: Mechanism Dissection Of How M2 Macrophages Increase the Hcc mentioning

confidence: 99%

M2 Macrophages Promote HCC Cells Invasion and Migration via miR-149-5p/MMP9 Signaling

Liu¹,

Yin²,

Ouyang³

et al. 2020

J. Cancer

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The roles of M2 macrophages on promoting tumor progression and chemotherapy resistance have been well studied in many cancers, such as pancreatic cancer, kidney cancer and so on, but its linkage to HCC cells still remains unclear. Here we found that M2 macrophages could alter miR-149-5p to increase MMP9 expression in HCC cells and mechanism dissection revealed that miR-149-5p might directly target the 3'UTR of MMP9-mRNA to suppress its translation. The in vivo orthotopic xenografts mouse model with oemiR-149-5p also validated in vitro data. Together, these findings suggest that M2 macrophages may through altering the miR-149-5p to promote HCC progression and targeting the M2 macrophages/ miR149-5P/MMP9 signaling may help in the development of the novel therapies to better suppress the HCC progression.

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Section: Mechanism Dissection Of How M2 Macrophages Increase the Hcc mentioning

confidence: 99%

M2 Macrophages Promote HCC Cells Invasion and Migration via miR-149-5p/MMP9 Signaling

Liu¹,

Yin²,

Ouyang³

et al. 2020

J. Cancer

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“…However, T cellspecific Cic null mice did not show T-ALL phenotypes up to 14 months of age 33 , suggesting that the loss of CIC in T cells may be insufficient to cause T-ALL, and CIC deficiency in other types of immune cells may contribute to disease onset in mice. Decreased CIC expression at the protein level is frequently observed in various types of cancer [19][20][21]28,46 . Moreover, the CIC protein levels are often not correlated with the mRNA levels within the same cancer samples, suggesting that CIC exhibits robust post-transcriptional regulation in cancer cells 19,21 .…”

Section: Cancermentioning

confidence: 99%

“…Decreased CIC expression at the protein level is frequently observed in various types of cancer [19][20][21]28,46 . Moreover, the CIC protein levels are often not correlated with the mRNA levels within the same cancer samples, suggesting that CIC exhibits robust post-transcriptional regulation in cancer cells 19,21 . Nuclear expression of CIC decreases gradually as prostate cancer (PC) becomes more aggressive 20 .…”

Section: Cancermentioning

confidence: 99%

“…CIC-DUX4 fusion proteins activate the expression of ETV1, ETV4, and ETV5, which encode oncogenic transcription factors 18 , thereby promoting cancer progression 17 . Many studies have verified that CIC functions as a tumor suppressor in various types of cancer [19][20][21][22][23][24][25][26][27][28] . Endogenous functions of CIC have been elucidated by examinations of the phenotypes of Cic mutant mice.…”

Section: Introductionmentioning

confidence: 99%

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Regulation and function of capicua in mammals

Lee

2020

Exp Mol Med

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Capicua (CIC) is an evolutionarily conserved transcription factor. CIC contains a high-mobility group (HMG) box that recognizes specific DNA sequences to regulate the expression of various target genes. CIC was originally identified in Drosophila melanogaster as a transcriptional repressor that suppresses the receptor tyrosine kinase signaling pathway. This molecule controls normal organ growth and tissue patterning as well as embryogenesis in Drosophila. Recent studies have also demonstrated its extensive functions in mammals. For example, CIC regulates several developmental and physiological processes, including lung development, abdominal wall closure during embryogenesis, brain development and function, neural stem cell homeostasis, T cell differentiation, and enterohepatic circulation of bile acids. CIC is also associated with the progression of various types of cancer and neurodegeneration in spinocerebellar ataxia type-1, systemic autoimmunity, and liver injury. In this review, I provide a broad overview of our current understanding of the regulation and functions of CIC in mammals and discuss future research directions.

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“…CIC is a high mobility group (HMG) box‐containing transcriptional repressor and preferentially binds to T(G/C)AATG(G/A)A DNA sequences through the HMG box in conjunction with the C1 domain . Although several studies have identified dozens of CIC target genes in mammalian cells, the polyoma enhancer activator 3 ( PEA3 ) group genes (ETS translocation variant [ ETV ] 1 , ETV4 , and ETV5 ) are the CIC target genes that have been most extensively studied in various types of cells, including CD4 + T cells . In mammals, CIC has been implicated in regulation of spinocerebellar ataxia type 1 neurodegeneration, lung alveolarization, learning and memory, and cancer progression .…”

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confidence: 99%

The Capicua/ETS Translocation Variant 5 Axis Regulates Liver‐Resident Memory CD8+ T‐Cell Development and the Pathogenesis of Liver Injury

Park

Kim

et al. 2019

Hepatology

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Liver‐resident memory T (liver TRM) cells exert protective immune responses following liver infection by malaria parasites. However, how these TRM cells are developed and what the consequence is if they are not properly maintained remain poorly understood. Here, we show that the transcriptional repressor, Capicua (CIC), controls liver CD8+ TRM cell development to maintain normal liver function. Cic‐deficient mice have a greater number of liver CD8+ TRM cells and liver injury phenotypes accompanied by increased levels of proinflammatory cytokine genes in liver tissues. Excessive formation of CD69+CD8+ TRM‐like cells was also observed in mice with acetaminophen‐induced liver injury (AILI). Moreover, expansion of liver CD8+ TRM cell population and liver injury phenotypes in T‐cell–specific Cic null mice were rescued by codeletion of ETS translocation variant [Etv]5 alleles, indicating that Etv5 is a CIC target gene responsible for regulation of CD8+ TRM cell development and liver function. We also discovered that ETV5 directly regulates expression of Hobit, a master transcription factor for TRM cell development, in CD8+ T cells. Conclusion: Our findings suggest the CIC‐ETV5 axis as a key molecular module that controls CD8+ TRM cell development, indicating a pathogenic role for CD8+ TRM cells in liver injury.

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Capicua suppresses hepatocellular carcinoma progression by controlling the ETV4–MMP1 axis

Abstract: Our study demonstrates that the CIC-ETV4-MMP1 axis is a regulatory module controlling HCC progression. (Hepatology 2018;67:2287-2301).

Cited by 75 publications

References 51 publications

M2 Macrophages Promote HCC Cells Invasion and Migration via miR-149-5p/MMP9 Signaling

M2 Macrophages Promote HCC Cells Invasion and Migration via miR-149-5p/MMP9 Signaling

Regulation and function of capicua in mammals

The Capicua/ETS Translocation Variant 5 Axis Regulates Liver‐Resident Memory CD8+ T‐Cell Development and the Pathogenesis of Liver Injury

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