scholarly journals Runt related transcription factor-1 plays a central role in vessel co-option of colorectal cancer liver metastases

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Miran Rada ◽  
Audrey Kapelanski-Lamoureux ◽  
Stephanie Petrillo ◽  
Sébastien Tabariès ◽  
Peter Siegel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Growth Patterns ◽  
Colorectal Cancer Liver Metastases ◽  
Related Transcription Factor ◽  
Transcription Factor 1

AbstractColorectal cancer liver metastasis (CRCLM) has two major histopathological growth patterns: angiogenic desmoplastic and non-angiogenic replacement. The replacement lesions obtain their blood supply through vessel co-option, wherein the cancer cells hijack pre-existing blood vessels of the surrounding liver tissue. Consequentially, anti-angiogenic therapies are less efficacious in CRCLM patients with replacement lesions. However, the mechanisms which drive vessel co-option in the replacement lesions are unknown. Here, we show that Runt Related Transcription Factor-1 (RUNX1) overexpression in the cancer cells of the replacement lesions drives cancer cell motility via ARP2/3 to achieve vessel co-option. Furthermore, overexpression of RUNX1 in the cancer cells is mediated by Transforming Growth Factor Beta-1 (TGFβ1) and thrombospondin 1 (TSP1). Importantly, RUNX1 knockdown impaired the metastatic capability of colorectal cancer cells in vivo and induced the development of angiogenic lesions in liver. Our results confirm that RUNX1 may be a potential target to overcome vessel co-option in CRCLM.

scholarly journals Doublesex- and Mab-3-Related Transcription Factor-1 Repression of Aromatase Transcription, a Possible Mechanism Favoring the Male Pathway in Tilapia

Endocrinology ◽  
2010 ◽  
Vol 151 (3) ◽  
pp. 1331-1340 ◽  
Author(s):  
De-Shou Wang ◽  
Lin-Yan Zhou ◽  
Tohru Kobayashi ◽  
Masaru Matsuda ◽  
Yasushi Shibata ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Hek 293 ◽  
Aromatase Gene ◽  
Estrogen Production ◽  
Testicular Differentiation ◽  
Related Transcription Factor ◽  
Transcription Factor 1

Doublesex- and Mab-3-related transcription factor-1 (Dmrt1) is an important transcription factor implicated in early testicular differentiation in vertebrates, but its target genes are largely unknown. In the Nile tilapia, estrogen is the natural inducer of ovarian differentiation. Our recent studies have shown that Forkhead-l2 up-regulated transcription of the Cyp19a1a gene (aromatase) in the gonads in a female-specific manner. However, the upstream factor(s) down-regulating Cyp19a1a expression during testicular differentiation remains unclear. In the present study, we used in vitro (promoter analysis) and in vivo (transgenesis and in situ hybridization) approaches to examine whether Dmrt1 inhibits Cyp19a1a’s transcriptional activity. The in vitro analysis using luciferase assays revealed that Dmrt1 repressed basal as well as Ad4BP/SF-1-activated Cyp19a1a transcription in HEK 293 cells. Luciferase assays with various deletions of Dmrt1 also showed that the Doublesex and Mab-3 domain is essential for the repression. In vitro-translated Dmrt1 and the nuclear extract from tilapia testis could directly bind to the palindrome sequence ACATATGT in the Cyp19a1a promoter, as determined by EMSAs. Transgenic overexpression of Dmrt1 in XX fish resulted in decreased aromatase gene expression, reduced serum estradiol-17β levels, retardation of the ovarian cavity’s development, varying degrees of follicular degeneration, and even a partial to complete sex reversal. Our results indicate that aromatase is one of the targets of Dmrt1. Dmrt1 suppresses the female pathway by repressing aromatase gene transcription and estrogen production in the gonads of tilapia and possibly other vertebrates.

scholarly journals New Insights into Cancer Targeted Therapy: Nodal and Cripto-1 as Attractive Candidates

2021 ◽  
Vol 22 (15) ◽  
pp. 7838
Author(s):  
Paola Arboretto ◽  
Michele Cillo ◽  
Antonio Leonardi
Keyword(s):  
Targeted Therapy ◽  
Cancer Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Differentiated Cells ◽  
Medical Need ◽  
Cancer Targeted Therapy

The transforming growth factor beta (TGF-β) signaling is fundamental for correct embryonic development. However, alterations of this pathway have been correlated with oncogenesis, tumor progression and sustaining of cancer stem cells (CSCs). Cripto-1 (CR-1) and Nodal are two embryonic proteins involved in TGF-β signaling. Their expression is almost undetectable in terminally differentiated cells, but they are often re-expressed in tumor cells, especially in CSCs. Moreover, cancer cells that show high levels of CR-1 and/or Nodal display more aggressive phenotypes in vitro, while in vivo their expression correlates with a worse prognosis in several human cancers. The ability to target CSCs still represents an unmet medical need for the complete eradication of certain types of tumors. Given the prognostic role and the selective expression of CR-1 and Nodal on cancer cells, they represent archetypes for targeted therapy. The aim of this review is to clarify the role of CR-1 and Nodal in cancer stem populations and to summarize the current therapeutic strategy to target CSCs using monoclonal antibodies (mAbs) or other molecular tools to interfere with these two proteins.

scholarly journals Downregulating Long Non-coding RNAs CTBP1-AS2 Inhibits Colorectal Cancer Development by Modulating the miR-93-5p/TGF-β/SMAD2/3 Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Qiankun Li ◽  
Wenjing Yue ◽  
Ming Li ◽  
Zhipeng Jiang ◽  
Zehui Hou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Luciferase Reporter ◽  
Reverse Transcription Pcr ◽  
Non Coding Rnas ◽  
And Function

Background: Colorectal cancer (CRC), the most commonly diagnosed cancer in the world, has a high mortality rate. In recent decades, long non-coding RNAs (lncRNAs) have been proven to exert an important effect on CRC growth. However, the CTBP1-AS2 expression and function in CRC are largely unknown.Materials and Methods: The CTBP1-AS2 and miR-93-5p expression in CRC and para-cancerous tissues was detected by reverse transcription-PCR. The expression of CTBP1-AS2, miR-93-5p and the transforming growth factor-beta (TGF-β)/small mothers against decapentaplegic 2/3 (SMAD2/3) pathway was selectively regulated to study the correlation between CTBP1-AS2 expression and prognosis of patients with CRC. CRC cell proliferation, apoptosis, and invasion were measured in vivo and in vitro. In addition, bioinformatics was applied to explore the targeting relationship between CTBP1-AS2 and miR-93-5p. The targeting binding sites between CTBP1-AS2 and miR-93-5p, as well as between miR-93-5p and TGF-β, were verified by the dual-luciferase reporter assay and the RNA immunoprecipitation experiment.Results: Compared with normal para-cancerous tissues, CTBP1-AS2 was considerably overexpressed in CRC tissues and was closely associated with worse survival of patients with CRC. Functionally, gain and loss in experiments illustrated that CTBP1-AS2 accelerated CRC cell proliferation and invasion and inhibited cell apoptosis. Mechanistically, CTBP1-AS2 regulated the malignant phenotype of tumor cells through the TGF-β/SMAD2/3 pathway. Moreover, miR-93-5p, as an endogenous competitive RNA of CTBP1-AS2, attenuated the oncogenic effects mediated by CTBP1-AS2.Conclusion: CTBP1-AS2 promotes the TGF-β/SMAD2/3 pathway activation by inhibiting miR-93-5p, thereby accelerating CRC development.

scholarly journals Tripartite motif containing 25 promotes proliferation and invasion of colorectal cancer cells through TGF-β signaling

2017 ◽  
Vol 37 (4) ◽  
Author(s):  
Nianfeng Sun ◽  
Yu Xue ◽  
Ting Dai ◽  
Xiding Li ◽  
Nanxiang Zheng
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Gastric Cancer Cells ◽  
Colorectal Cancer Cells ◽  
Tripartite Motif ◽  
Proliferation And Invasion

Tripartite motif containing 25 (TRIM25) is a member of TRIM proteins and functions as an E3 (ubiquitin ligase). It has been found to act as an oncogene in gastric cancer cells and is abnormally expressed in cancers in female reproductive system. Here, we investigated the function of TRIM25 in colorectal cancer. TRIM25 was found to be significantly up-regulated in colorectal cancer tissues and cancer cell lines through real-time PCR assay. Colorectal cancer cells (CRCs) overexpressing TRIM25 exhibited a two-fold higher proliferation and migration rate compared with their parental lines in vitro. Moreover, TRIM25 also promoted tumor progression in vivo. Further study indicated that TRIM25 worked through positively regulating transforming growth factor β (TGF-β) signaling pathway to regulate the proliferation and invasion of CRCs. In summary, our results indicate that TRIM25 also acts as an oncogene in colorectal cancer and it functions through TGF-β signaling pathway. Thus, TRIM25 represents potential targets for the treatment of colorectal cancer.

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