MCPIP1 Downregulation in Clear Cell Renal Cell Carcinoma Promotes Vascularization and Metastatic Progression

Marona, Paulina; Górka, Judyta; Mazurek, Zofia; Wilk, Wacław; Ryś, Janusz; Majka, Marcin; Jura, Jolanta; Miękus, Katarzyna

doi:10.1158/0008-5472.can-16-3190

Cited by 63 publications

(81 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Emerging evidence has revealed the function of CXCL12-CXCR4 axis in cancer progression, especially regarding tumor metastasis (24)(25)(26). Studies have shown that aberrantly expressed CXCL12 or CXCR4 was correlated with tumor hematogenous spread and prognosis in multiple solid malignancies such as breast cancer, pancreatic cancer, and prostate cancer (24,(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of CXCL12 Plays a Critical Role in Mediating Tumor Progression and the Immune Response In Osteosarcoma

Zhan

et al. 2018

Cancer Research

View full text Add to dashboard Cite

The mechanism by which osteosarcomas metastasize is elusive, and challenges remain regarding its treatment with modalities including immunotherapy. CXCL12 is deeply involved in the process of tumor metastasis and T-cell homing, which is driven by a chemokine gradient, but healthy bones are supposed to preferentially express CXCL12. Here, we show for the first time that osteosarcomas epigenetically downregulate CXCL12 expression via DNA methyltransferase 1 (DNMT1) and consequently acquire the ability to metastasize and to impair cytotoxic T-cell homing to the tumor site. Analysis of human osteosarcoma cases further revealed that CXCL12 expression strongly correlated with overall survival. Evaluations on fresh human chemotherapy-free osteosarcoma samples also showed a positive correlation between CXCL12 concentration and the number of intratumoral lymphocytes. Critically, treatment targeting DNMT1 in immunocompetent mouse models significantly elevated expression of CXCL12 in tumors, resulting in a robust immune response and consequently eradicating early lung metastases in addition to suppressing subcutaneous tumor growth. These antitumor effects were abrogated by CXCL12-CXCR4 blockade or CD8 T-cell depletion. Collectively, our data show that CXCL12 regulation plays a significant role in both tumor progression and immune response, and targeting CXCL12 is promising for therapeutics against osteosarcoma. Epigenetic regulation of CXCL12 controls metastasis and immune response in osteosarcoma, suggesting epigenetic therapies or therapies targeting CXCL12 have potential for therapeutic intervention in osteosarcoma. .

show abstract

Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of CXCL12 Plays a Critical Role in Mediating Tumor Progression and the Immune Response In Osteosarcoma

Zhan

et al. 2018

Cancer Research

View full text Add to dashboard Cite

show abstract

“…It was shown that MCPIP1 regulates inflammatory processes by controlling transcripts coding for proinflammatory cytokines, such as IL-1beta, IL-6, IL-12p40, IL-2 and transcription factors controlling proinflammatory processes, such as the c-Rel subunit of NFκB [4][5][6][7]. Furthermore, MCPIP1 regulates processes important in cancer development, such as cell metabolism, proliferation, and angiogenesis [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Losko

Dolicka

Pydyn

et al. 2019

Cell. Mol. Life Sci.

Self Cite

View full text Add to dashboard Cite

Obesity is considered a serious chronic disease, associated with an increased risk of developing cardiovascular diseases, non-alcoholic fatty liver disease and type 2 diabetes. Monocyte chemoattractant protein-1-induced protein-1 (MCPIP1) is an RNase decreasing stability of transcripts coding for inflammation-related proteins. In addition, MCPIP1 plays an important role in the regulation of adipogenesis in vitro by reducing the expression of key transcription factors, including C/EBPβ. To elucidate the role of MCPIP1 in adipocyte biology, we performed RNA-Seq and proteome analysis in 3T3-L1 adipocytes overexpressing wild-type ( WT MCPIP1) and the mutant form of MCPIP1 protein ( D141N MCPIP1). Our RNA-Seq analysis followed by confirmatory Q-RT-PCR revealed that elevated MCPIP1 levels in 3T3-L1 adipocytes upregulated transcripts encoding proteins involved in signal transmission and cellular remodeling and downregulated transcripts of factors involved in metabolism. These data are consistent with our proteomic analysis, which showed that MCPIP1 expressing adipocytes exhibit upregulation of proteins involved in cellular organization and movement and decreased levels of proteins involved in lipid and carbohydrate metabolism. Moreover, MCPIP1 adipocytes are characterized by decreased level of insulin receptor, reduced insulin-induced Akt phosphorylation, as well as depleted Glut4 level and impaired glucose uptake. Overexpression of Glut4 in 3T3-L1 cells expressed WT MCPIP1 rescued adipogenesis. Interestingly, we found decreased level of MCPIP1 along with an increase in body mass index in subcutaneous adipose tissue. The presented data show a novel role of MCPIP1 in modulating insulin sensitivity in adipocytes. Overall, our findings demonstrate that MCPIP1 is an important regulator of adipogenesis and adipocyte metabolism.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

show abstract

“…Low MCPIP1 levels have been reported in neuroblastoma [ 12 ], breast cancer [ 13 ] and ccRCC [ 4 , 14 ]. MCPIP1 inhibits growth of ccRCC and neuroblastoma cell lines [ 4 , 12 ] by enhancing the decay of anti-apoptotic gene transcripts, including Bcl2L1, Bcl2A1, RelB, Birc3, and Bcl3 [ 13 ] and negatively regulating the rate of metabolism and angiogenesis [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

RNA sequencing reveals widespread transcriptome changes in a renal carcinoma cell line

et al. 2018

Self Cite

View full text Add to dashboard Cite

We used RNA sequencing (RNA-Seq) technology to investigate changes in the transcriptome profile in the Caki-1 clear cell renal cell carcinoma (ccRCC) cells, which overexpress monocyte chemoattractant protein-induced protein 1 (MCPIP1). RNA-Seq data showed changes in 11.6% and 41.8% of the global transcriptome of Caki-1 cells overexpressing wild-type MCPIP1 or its D141N mutant, respectively. Gene ontology and KEGG pathway functional analyses showed that these transcripts encoded proteins involved in cell cycle progression, protein folding in the endoplasmic reticulum, hypoxia response and cell signalling. We identified 219 downregulated transcripts in MCPIP1-expressing cells that were either unchanged or upregulated in D141N-expressing cells. We validated downregulation of 15 transcripts belonging to different functional pathways by qRT-PCR. The growth and viability of MCPIP1-expressing cells was reduced because of elevated p21Cip1 levels. MCPIP1-expressing cells also showed reduced levels of DDB1 transcript that encodes component of the E3 ubiquitin ligase that degrades p21Cip1. These results demonstrate that MCPIP1 influences the growth and viability of ccRCC cells by increasing or decreasing the transcript levels for proteins involved in cell cycle progression, protein folding, hypoxia response, and cell signaling.

show abstract

MCPIP1 Downregulation in Clear Cell Renal Cell Carcinoma Promotes Vascularization and Metastatic Progression

Cited by 63 publications

References 49 publications

Epigenetic Regulation of CXCL12 Plays a Critical Role in Mediating Tumor Progression and the Immune Response In Osteosarcoma

Epigenetic Regulation of CXCL12 Plays a Critical Role in Mediating Tumor Progression and the Immune Response In Osteosarcoma

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

RNA sequencing reveals widespread transcriptome changes in a renal carcinoma cell line

Contact Info

Product

Resources

About