scholarly journals The Emerging Role of Inhibitor of Growth 4 as a Tumor Suppressor in Multiple Human Cancers

2015 ◽  
Vol 36 (2) ◽  
pp. 409-422 ◽  
Author(s):  
Shiyun Cui ◽  
Yanping Gao ◽  
Kai Zhang ◽  
Jing Chen ◽  
Rui Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factors ◽  
Tumor Suppressor ◽  
Gene Deletion ◽  
Critical Role ◽  
Chromatin Modification ◽  
Transcriptional Dysregulation ◽  
Tumorigenesis And Progression ◽  
Nf Kappab

Inhibitor of growth 4 (ING4), a member of the conserved ING family, has been identified as an important tumor suppressor since it plays a critical role in the regulation of chromatin modification, cell proliferation, angiogenesis and cell migration. Some observations suggest that ING4 acts as a key regulator of tumorigenesis through modifying gene transcription in part by regulating the transcription factors p53 and NF-kappaB (NF-κB). However, these models have yet to be substantiated by further investigations. Numerous reports describe the reduced expression of ING4 in cancers, and the responsible mechanisms are involved in gene deletion, mutation, transcriptional and post-transcriptional dysregulation. This review aims to summarize the recent published literature that investigates the role of ING4 in regulating tumorigenesis and progression, and explore its potential for cancer treatment.

scholarly journals BRN2 is a non-canonical melanoma tumor-suppressor

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Michael Hamm ◽  
Pierre Sohier ◽  
Valérie Petit ◽  
Jérémy H. Raymond ◽  
Véronique Delmas ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Tumor Suppressor ◽  
The Other ◽  
Pi3k Signaling ◽  
Melanoma Tumor ◽  
Temporal Regulation ◽  
Metastatic Colonization ◽  
Pou Domain

AbstractWhile the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600EPtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.

scholarly journals A critical role of AREG for bleomycin-induced skin fibrosis

2021 ◽  
Author(s):  
Mary Yinghua Zhang ◽  
Shuyi Fang ◽  
Hongyu Gao ◽  
Xiaoli Zhang ◽  
Dongsheng Gu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wound Healing ◽  
Oral Mucosa ◽  
Healing Process ◽  
Critical Role ◽  
Skin Fibrosis ◽  
Wound Healing Process ◽  
Organ Function ◽  
Signaling Axis

ABSTRACTWe report our discovery of an important player in the development of skin fibrosis, a hallmark of scleroderma. Scleroderma is a fibrotic disease, affecting 70,000 to 150,000 Americans. Fibrosis is a pathological wound healing process that produces an excessive extracellular matrix to interfere with normal organ function. Fibrosis contributes to nearly half of human mortality. Scleroderma has heterogeneous phenotypes, unpredictable outcomes, no validated biomarkers, and no effective treatment. Thus, strategies to slow down scleroderma progression represent an urgent medical need. While a pathological wound healing process like fibrosis leaves scars and weakens organ function, oral mucosa wound healing is a scarless process. After re-analyses of gene expression datasets from oral mucosa wound healing and skin fibrosis, we discovered that several pathways constitutively activated in skin fibrosis are transiently induced during oral mucosa wound healing process, particularly the amphiregulin (Areg) gene. Areg expression is upregulated ~10 folds 24hrs after oral mucosa wound but reduced to the basal level 3 days later. During bleomycin-induced skin fibrosis, a commonly used mouse model for skin fibrosis, Areg is up-regulated throughout the fibrogenesis and is associated with elevated cell proliferation in the dermis. To demonstrate the role of Areg for skin fibrosis, we used mice with Areg knockout, and found that Areg deficiency essentially prevents bleomycin-induced skin fibrosis. We further determined that bleomycin-induced cell proliferation in the dermis was not observed in the Areg null mice. Furthermore, we found that inhibiting MEK, a downstream signaling effector of Areg, by selumetinib also effectively blocked bleomycin-based skin fibrosis model. Based on these results, we concluded that the Areg-EGFR-MEK signaling axis is critical for skin fibrosis development. Blocking this signaling axis may be effective in treating scleroderma.

scholarly journals Unveiling role of sphingosine-1-phosphate receptor 2 as a brake of epithelial stem cell proliferation and a tumor suppressor in colorectal cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Luciana Petti ◽  
Giulia Rizzo ◽  
Federica Rubbino ◽  
Sudharshan Elangovan ◽  
Piergiuseppe Colombo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Tumor Suppressor ◽  
Normal Mucosa ◽  
Intestinal Stem Cells ◽  
Intestinal Epithelial ◽  
Sphingosine 1 Phosphate

Abstract Background Sphingosine-1-phosphate receptor 2 (S1PR2) mediates pleiotropic functions encompassing cell proliferation, survival, and migration, which become collectively de-regulated in cancer. Information on whether S1PR2 participates in colorectal carcinogenesis/cancer is scanty, and we set out to fill the gap. Methods We screened expression changes of S1PR2 in human CRC and matched normal mucosa specimens [N = 76]. We compared CRC arising in inflammation-driven and genetically engineered models in wild-type (S1PR2+/+) and S1PR2 deficient (S1PR2−/−) mice. We reconstituted S1PR2 expression in RKO cells and assessed their growth in xenografts. Functionally, we mimicked the ablation of S1PR2 in normal mucosa by treating S1PR2+/+ organoids with JTE013 and characterized intestinal epithelial stem cells isolated from S1PR2−/−Lgr5-EGFP- mice. Results S1PR2 expression was lost in 33% of CRC; in 55%, it was significantly decreased, only 12% retaining expression comparable to normal mucosa. Both colitis-induced and genetic Apc+/min mouse models of CRC showed a higher incidence in size and number of carcinomas and/or high-grade adenomas, with increased cell proliferation in S1PR2−/− mice compared to S1PR2+/+ controls. Loss of S1PR2 impaired mucosal regeneration, ultimately promoting the expansion of intestinal stem cells. Whereas its overexpression attenuated cell cycle progression, it reduced the phosphorylation of AKT and augmented the levels of PTEN. Conclusions In normal colonic crypts, S1PR2 gains expression along with intestinal epithelial cells differentiation, but not in intestinal stem cells, and contrasts intestinal tumorigenesis by promoting epithelial differentiation, preventing the expansion of stem cells and braking their malignant transformation. Targeting of S1PR2 may be of therapeutic benefit for CRC expressing high Lgr5. Graphical Abstract. Schematic drawing of the role of S1PR2 in normal mucosa and colorectal cancer. In the normal mucosa, S1PR2 is highly expressed by differentiated cells at the upper region of both colon and intestinal crypts (S1PR2 ON), but not by the undifferentiated stem cell at the base of the crypts (S1PR2 OFF), in which acts as a negative proliferative regulator promoting epithelial differentiation. Its loss leads to the expansion of stem cells and reduced levels of PTEN and Axin-2, two negative regulators respectively of PI3K/AKT and Wnt signaling that control β-catenin signaling. The translocation of β-catenin into the nucleus promotes the transcription of target genes involved in the proliferation and malignant transformation. Thereby, S1PR2 works in the intestine as a tumor suppressor

Abstract 4294: Using the zebrafish model to determine the role of the HACE1 tumor suppressor in apoptosis, cell proliferation and development

2011 ◽  
Author(s):  
Lindsay A. McDonald ◽  
Sahar Da'as ◽  
Paul D'Alessandro ◽  
Poul H. Sorensen ◽  
Jason N. Berman
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Zebrafish Model

scholarly journals STAT3 and STAT5 Activation in Solid Cancers

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1428 ◽  
Author(s):  
Sebastian Igelmann ◽  
Heidi Neubauer ◽  
Gerardo Ferbeyre
Keyword(s):  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Critical Role ◽  
Control Cell ◽  
Cytokine Signaling ◽  
Specific Gene ◽  
Mitochondrial Functions ◽  
Context Dependent

The Signal Transducer and Activator of Transcription (STAT)3 and 5 proteins are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context-dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association with survival in cancer patients. The molecular mechanisms that underpin the oncogenic activity of STAT3/5 signaling include the regulation of genes that control cell cycle and cell death. However, recent advances also highlight the critical role of STAT3/5 target genes mediating inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling, including tyrosine phosphatases, the sumo ligase Protein Inhibitor of Activated STAT3 (PIAS3), the E3 ubiquitin ligase TATA Element Modulatory Factor/Androgen Receptor-Coactivator of 160 kDa (TMF/ARA160), the miRNAs miR-124 and miR-1181, the Protein of alternative reading frame 19 (p19ARF)/p53 pathway and the Suppressor of Cytokine Signaling 1 and 3 (SOCS1/3) proteins. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated with STAT3/5 signaling, explaining their context-dependent association with tumor progression both in human cancers and animal models.

Critical role of farnesoid X receptor for hepatocellular carcinoma cell proliferation

2012 ◽  
Vol 152 (6) ◽  
pp. 577-586 ◽  
Author(s):  
T. Fujino ◽  
A. Takeuchi ◽  
A. Maruko-Ohtake ◽  
Y. Ohtake ◽  
J. Satoh ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Carcinoma Cell ◽  
Critical Role ◽  
Farnesoid X Receptor ◽  
Hepatocellular Carcinoma Cell

C/EBPb Is a Critical Mediator of Resistance to IMiD® Immunomodulatory Compounds and Affected by IMiD Compounds Via Control of Protein Translation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 135-135
Author(s):  
Shirong Li ◽  
Rekha Pal ◽  
Sara Monaghan ◽  
Peter Schafer ◽  
Hongjiao Ouyang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Translational Control ◽  
Critical Role ◽  
Protein Translation ◽  
Thymidine Uptake ◽  
Double Labeling ◽  
Equity Ownership

Abstract Abstract 135 Background: Lenalidomide and pomalidomide are IMiD® immunomodulatory compounds that have been shown to be highly active in the treatment of multiple myeloma (MM). IMiD compounds exert their anti-tumor effects via acting on costimulatory proteins of T cells and NK cells, augmenting both the adaptive and innate immune system. But the mechanisms by which IMiD compounds directly inhibit MM cell proliferation are still unclear. Here we focused on the direct effects of IMiD compounds alone on MM cells. Results and Methods: We found that IMiDs, at concentrations as low as 0.01 μ M, induce significant inhibition of DNA synthesis in MM cells as shown by thymidine uptake. Since our previous work demonstrated that C/EBPβ is an important transcription factor which controls the growth and proliferation of myeloma cells, we analyzed the effects of IMiD compounds on C/EBPβ. We found that both pomalidomide and lenalidomide significantly decreased the protein level of C/EBPβ LAP-isoform in MM cell lines and primary MM cells. IMiD compound-induced suppression of C/EBPβ protein expression led to impaired transcription of the downstream IRF4, and subsequently to downregulation of BLIMP1 and XBP1, which are all critical for MM survival. To confirm our findings in vivo, we analyzed IRF4 expression by double labeling (IRF4+/CD138+) immunohistochemical staining of bone marrow biopsy samples of 23 myeloma patients prior to therapy and during therapy with lenalidomide. During lenalidomide therapy, the bone marrow MM cells showed a significantly weaker staining intensity for IRF4 in comparison to prior therapy. This was quantified by a significant (p<0.001) decrease of the staining score from 176 to 152, respectively. To confirm the critical role of C/EBPβ in MM we stably overexpressed C/EBPβ in MM cells. Overexpression of C/EBPβ prevented IMiD compound-induced inhibition of MM cell proliferation, indicating that C/EBPβ is critical in mediating resistance to IMiD compounds. This was supported by the fact that C/EBPβ was not down regulated in IMiD-resistant cell lines by IMiD treatment. Dissection of the C/EBPβ protein regulation revealed that IMiD compounds shut down C/EBPβ protein translation by decreasing eIF-4E. Knockdown experiments of eIF-4e resulted in downregulation of C/EBPβ, suggesting that C/EBPβ is under translational control in MM. Conclusions: Our studies, for the first time, provide evidence that IMiD compounds inhibit MM cell proliferation and survival by affecting the translation of C/EBPβ and subsequently multiple downstream transcription factors including IRF4, BLIMP1 and XBP1. Due to the critical role of C/EBPβ in mediating effects of IMiD compounds in MM, it might be a target to overcome drug resistance to IMiD compounds. The fact that pomalidomide can overcome resistance to lenalidomide in MM requires still further evaluation. Disclosures: Schafer: Celgene Corporation: Employment, Equity Ownership. Mapara:Gentium: Equity Ownership. Lentzsch:Celgene Corp: Research Funding.

Mir-23b Plays a Critical Role As a Tumor Suppressor miRNA In Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 122-122 ◽  
Author(s):  
Mariateresa Fulciniti ◽  
Nicola Amodio ◽  
Rajya Bandi ◽  
Rao H. Prabhala ◽  
Sophia Adamia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Tumor Suppressor ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Myeloma Cells ◽  
Equity Ownership

Abstract Deregulated expression of microRNAs (miR) is a hallmark of cancer. Tumor suppressor miRNAs are generally down-regulated in cancer cells compared to their normal counterpart, and their enforced expression indeed represents a promising strategy for cancer treatment. We have found miR-23b to be downregulated in CD138+ myeloma cells from 38 multiple myeloma (MM) patients and 18 plasma cell leukemia (PCL) patients compared to normal PCs. Decreased expression of miR-23b was further confirmed in an independent dataset of 66 MM patients by TaqMan miRNA assays. The downregulation of miR-23b expression was also observed in several myeloma cells lines when compared with PBMC and BMSC. Interestingly, interaction of BMSC with MM cells resulted in further decrease in miR-23b expression in both cell types. Moreover, Interleukin-6 (IL-6) also suppressed the expression of miR-23b in a time- and dose- dependent pattern, indicating that the human bone marrow microenvironment (huBMM) modulates miR-23b levels. miR-23b is commonly repressed in autoimmune conditions by IL-17, a cytokine shown to promote myeloma cell growth and inhibit its immune function. We have indeed observed further decrease in miR-23b expression in MM cells after IL-17 treatment for 24 hours. We have also observed downregulation of miR-23b in CD19+ Waldenstrom’s Macroglobulinemia (WM) cells compared to CD19+ B cells from healthy donors, which was further decreased in the presence of components of the WM bone marrow milieu. We further assessed the functional significance of miR-23b by both gain- and loss-of-function studies. A significant decrease in cell proliferation and survival, along with induction of caspase 3/7 activity was observed over time in miR-23b mimic–transfected myeloma (H929, KMS11) and WM cell lines (MWCL1) with low miR-23b expression. At the molecular level, we have identified Sp1, a transcription factor endowed with oncogenic activity in MM and WM, as a target of miR-23b. Expression of miR-23b decreased Sp1 mRNA levels via 3’UTR binding, as assessed in luciferase reporter assays. On the other hand, genetic and/or pharmacological inhibition of Sp1 led to miR-23b upregulation, thus highlighting the occurrence of a feedback loop between miR-23b and its target. Of note, miR-23b transfection significantly reduced Sp1-driven NF-kB activity in MM and WM cells. Finally, c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, has been shown to transcriptionally repress miR-23b. Moreover, treatment with the demethylating agent 5-aza-deoxycitidine significantly increase the expression of miR-23b in MM1S and KMS-11 cells suggesting that promoter methylation may be an additional mechanism of miR-23b suppression in myeloma. Thus MYC-dependent miR-23b repression in myeloma cells may allow activation of oncogenic transcription factors Sp1 and NF-κB, representing the first feed forward loop with critical growth and survival role in myeloma. Taken together, these data support a model in which the humoral environment reduces miR-23b expression in tumor cells, suggesting a tumor suppressor role in MM and WM and highlighting the potential of a miR-23b-based replacement therapy to treat these hematologic malignancies. Disclosures: Anderson: gilead: Consultancy; onyx: Consultancy; celgene: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership.

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