MicroRNA-146a limits tumorigenic inflammation in colorectal cancer

AbstractChronic inflammation can drive tumor development. Here, we have identified microRNA-146a (miR-146a) as a major negative regulator of colonic inflammation and associated tumorigenesis by modulating IL-17 responses. MiR-146a-deficient mice are susceptible to both colitis-associated and sporadic colorectal cancer (CRC), presenting with enhanced tumorigenic IL-17 signaling. Within myeloid cells, miR-146a targets RIPK2, a NOD2 signaling intermediate, to limit myeloid cell-derived IL-17-inducing cytokines and restrict colonic IL-17. Accordingly, myeloid-specific miR-146a deletion promotes CRC. Moreover, within intestinal epithelial cells (IECs), miR-146a targets TRAF6, an IL-17R signaling intermediate, to restrict IEC responsiveness to IL-17. MiR-146a within IECs further suppresses CRC by targeting PTGES2, a PGE2 synthesis enzyme. IEC-specific miR-146a deletion therefore promotes CRC. Importantly, preclinical administration of miR-146a mimic, or small molecule inhibition of the miR-146a targets, TRAF6 and RIPK2, ameliorates colonic inflammation and CRC. MiR-146a overexpression or miR-146a target inhibition represent therapeutic approaches that limit pathways converging on tumorigenic IL-17 signaling in CRC.

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LAT1 and ASCT2 Related microRNAs as Potential New Therapeutic Agents against Colorectal Cancer Progression

Biomedicines ◽

10.3390/biomedicines9020195 ◽

2021 ◽

Vol 9 (2) ◽

pp. 195

Author(s):

Francisca Dias ◽

Cristina Almeida ◽

Ana Luísa Teixeira ◽

Mariana Morais ◽

Rui Medeiros

Keyword(s):

Colorectal Cancer ◽

Amino Acid ◽

Cancer Progression ◽

Cell Metabolism ◽

Tumor Development ◽

Amino Acid Transporters ◽

Epigenetic Alterations ◽

Therapeutic Approaches ◽

Colorectal Cancer Progression ◽

Made In

The development and progression of colorectal cancer (CRC) have been associated with genetic and epigenetic alterations and more recently with changes in cell metabolism. Amino acid transporters are key players in tumor development, and it is described that tumor cells upregulate some AA transporters in order to support the increased amino acid (AA) intake to sustain the tumor additional needs for tumor growth and proliferation through the activation of several signaling pathways. LAT1 and ASCT2 are two AA transporters involved in the regulation of the mTOR pathway that has been reported as upregulated in CRC. Some attempts have been made in order to develop therapeutic approaches to target these AA transporters, however none have reached the clinical setting so far. MiRNA-based therapies have been gaining increasing attention from pharmaceutical companies and now several miRNA-based drugs are currently in clinical trials with promising results. In this review we combine a bioinformatic approach with a literature review in order to identify a miRNA profile with the potential to target both LAT1 and ASCT2 with potential to be used as a therapeutic approach against CRC.

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SOX9 directly regulates IGFBP-4 in the intestinal epithelium

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00086.2013 ◽

2013 ◽

Vol 305 (1) ◽

pp. G74-G83 ◽

Cited By ~ 20

Author(s):

Zhongcheng Shi ◽

Chi-I Chiang ◽

Toni-Ann Mistretta ◽

Angela Major ◽

Yuko Mori-Akiyama

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Epithelial Cells ◽

Target Genes ◽

Intestinal Epithelial Cells ◽

Neutralizing Antibody ◽

Intestinal Epithelial ◽

Loss Of Function ◽

Deficient Mice

SOX9 regulates cell lineage specification by directly regulating target genes in a discrete number of tissues, and previous reports have shown cell proliferative and suppressive roles for SOX9. Although SOX9 is expressed in colorectal cancer, only a few direct targets have been identified in intestinal epithelial cells. We previously demonstrated increased proliferation in Sox9-deficient crypts through loss-of-function studies, indicating that SOX9 suppresses cell proliferation. In this study, crypt epithelial cells isolated from Sox9-deficient mice were used to identify potential target genes of SOX9. Insulin-like growth factor (IGF)-binding protein 4 (IGFBP-4), an inhibitor of the IGF/IGF receptor pathway, was significantly downregulated in Sox9-deficient intestinal epithelial cells and adenoma cells of Sox9-deficient Apc Min/+ mice. Immunolocalization experiments revealed that IGFBP-4 colocalized with SOX9 in mouse and human intestinal epithelial cells and in specimens from patients with primary colorectal cancer. Reporter assays and chromatin immunoprecipitation demonstrated direct binding of SOX9 to the IGFBP-4 promoter. Overexpression of SOX9 attenuated cell proliferation, which was restored following treatment with a neutralizing antibody against IGFBP-4. These results suggest that SOX9 regulates cell proliferation, at least in part via IGFBP-4. Furthermore, the antiproliferative effect of SOX9 was confirmed in vivo using Sox9-deficient mice, which showed increased tumor burden when bred with Apc Min/+ mice. Our results demonstrate, for the first time, that SOX9 is a transcriptional regulator of IGFBP-4 and that SOX9-induced activation of IGFBP-4 may be one of the mechanisms by which SOX9 suppresses cell proliferation and progression of colon cancer.

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A30 INHIBITION OF NF-KB SIGNALING IN DCLK1+ CELLS PROMOTES COLONIC INFLAMMATION AND COLITIS-ASSOCIATED CANCER

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwz047.029 ◽

2020 ◽

Vol 3 (Supplement_1) ◽

pp. 37-38

Author(s):

H Good ◽

A E Shin ◽

L Zhang ◽

S Asfaha

Keyword(s):

Colorectal Cancer ◽

Protective Role ◽

Intestinal Epithelial ◽

Tumor Initiation ◽

Colonic Inflammation ◽

Dss Colitis ◽

Histological Damage ◽

Tuft Cell ◽

Tuft Cells ◽

Pathway Inhibition

Abstract Background Colorectal cancer (CRC) is the 2nd leading cause of cancer death in Canada. A major risk factor for this disease is chronic inflammation. Despite the clear link between inflammation and cancer, the exact mechanism by which colitis leads to cancer is unknown. Our group has previously shown that a rare cell type in the gut marked by the expression of doublecortin-like kinase-1 (Dclk1) and known as a tuft cell, is quiescent, long-lived, and resistant to proliferation even upon mutation of the tumor suppressor APC. Interestingly, in the setting of colitis, these APC-mutated tuft cells become powerful cancer-initiating cells, but the mechanism by which this occurs is not known. NF-kB signaling is a major inflammatory pathway active in colitis and that has been linked to colorectal cancer. Inhibition of the NF-kB pathway in intestinal epithelial cells has also been shown to inhibit tumor initiation in a mouse model of colitis-associated cancer (Greten et al., 2004). Aims In the present study, we aim to examine the effect of NF-kB inhibition in tuft cells on colitis-associated cancer. Methods Dclk1CreERT2/APCf/f mice were crossed to IKK-β f/f mice and administered tamoxifen to conditionally knockout the function of both APC and IKK-β in tuft cells. Mice were then exposed to the colitis-inducing agent dextran sodium sulfate (DSS) to induce tumorigenesis. Approximately 16 weeks post-tamoxifen, colonic tumor number and size were analyzed to determine the effect of NF-kB pathway inhibition on tumor initiation and growth, respectively. Extent of inflammation was assessed by myeloperoxidase (MPO) activity and histological damage, and colonic tissue was collected for measurement of inflammatory mediators by qRT-PCR at both acute and long-term time points. Results Interestingly, at baseline we detected increased MPO activity in Dclk1CreERT2/APCf/f/IKK-β f/f mice compared to control mice, suggesting that inhibition of NF-kB in Dclk1+ cells may increase basal colonic inflammation. Consistent with this observation, inhibition of the NF-kB pathway also resulted in an increased number of tuft cell-derived tumors, with no observed change in tumor size. Acutely, we also observed an exacerbation of DSS-colitis in Dclk1CreERT2/APCf/f/IKK-β f/f mice, as detected by elevated MPO activity, increased histological damage, and reduced colon length compared to wildtype (IKK-β +/+) controls. Conclusions These data suggest that Dclk1+ cell-specific NF-kB signaling plays a key protective role against colitis and colitis-associated tumorigenesis. Targeting the NF-kB pathway may reduce the severity of colitis and the incidence of colitis-associated cancer. Funding Agencies CIHR

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NDRG2 Regulates Adherens Junction Integrity to Restrict Colitis and Tumorigenesis

10.1101/473397 ◽

2018 ◽

Author(s):

Mengying Wei ◽

Yongzheng Ma ◽

Liangliang Shen ◽

Yuqiao Xu ◽

Lijun Liu ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Metastasis ◽

Tumor Development ◽

Adherens Junction ◽

Suppressor Gene ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Epithelial Barrier Function ◽

Gut Homeostasis ◽

E Cadherin

ABSTRACTParacellular barriers play an important role in the pathogenesis of IBDs and maintain gut homeostasis. N-myc downstream-regulated gene 2 (NDRG2) has been reported to be a tumor suppressor gene and inhibits colorectal cancer metastasis. However, whether NDRG2 affects colitis initiation and colitis-associated colorectal cancer is unclear. Here, We found that intestine-specific Ndrg2 deficiency caused mild spontaneous colitis with ageing, aggravated DSS and TNBS induced colitis, increased AOM-DSS induced colitis-associated tumor. Ndrg2 loss led to adherens junction (AJ) structure destruction via E-cadherin expression attenuation, resulting in diminished epithelial barrier function and increased intestinal epithelial permeability. Mechanistically, NDRG2 enhancing the interaction of E3 ligase FBXO11 with Snail, the repressor of E-cadherin, to promote Snail degradation by ubiquitination, and maintained E-cadherin expression. In human ulcerative colitis patients, reduced NDRG2 expression is positively correlated with severe inflammation. These findings demonstrate that NDRG2 is an essential colonic epithelial barrier regulator and plays important role in gut homeostasis maintenance and colitis-associated tumor development.SUMMARYAdherens junctoin (AJ) as the key part of intestinal epithelial barrier plays important role in the pathogenesis of IBDs. Intestinal specific Ndrg2 loss attenuates E-cadherin expression and disrupts the integrity of AJ structure which is feasible for colitis and tumor development.

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The Macrophages-Microbiota Interplay in Colorectal Cancer (CRC)-Related Inflammation: Prognostic and Therapeutic Significance

International Journal of Molecular Sciences ◽

10.3390/ijms21186866 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6866

Author(s):

Silvia Mola ◽

Chiara Pandolfo ◽

Antonio Sica ◽

Chiara Porta

Keyword(s):

Colorectal Cancer ◽

Tumor Development ◽

Prognostic Indicators ◽

Functional Heterogeneity ◽

Therapeutic Approaches ◽

Effector Cells ◽

New Therapeutic Approaches ◽

Cancer Types ◽

Macrophage Subtypes ◽

Main Population

Tumor-associated macrophages (TAMs) are the main population of myeloid cells infiltrating solid tumors and the pivotal orchestrators of cancer-promoting inflammation. However, due to their exceptional plasticity, macrophages can be also key effector cells and powerful activators of adaptive anti-tumor immunity. This functional heterogeneity is emerging in human tumors, colorectal cancer (CRC) in particular, where the dynamic co-existence of different macrophage subtypes influences tumor development, outcome, and response to therapies. Intestinal macrophages are in close interaction with enteric microbiota, which contributes to carcinogenesis and affects treatment outcomes. This interplay may be particularly relevant in CRC, one of the most prevalent and lethal cancer types in the world. Therefore, both macrophages and intestinal microbiota are considered promising prognostic indicators and valuable targets for new therapeutic approaches. Here, we discuss the current understanding of the molecular circuits underlying the interplay between macrophages and microbiota in CRC development, progression, and response to both conventional therapies and immunotherapies.

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VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer

Journal of Experimental Medicine ◽

10.1084/jem.20100438 ◽

2010 ◽

Vol 207 (13) ◽

pp. 2855-2868 ◽

Cited By ~ 99

Author(s):

Maximilian J. Waldner ◽

Stefan Wirtz ◽

André Jefremow ◽

Moritz Warntjen ◽

Clemens Neufert ◽

...

Keyword(s):

Colon Cancer ◽

Cell Proliferation ◽

Growth Factor ◽

Epithelial Cells ◽

Tumor Development ◽

Sporadic Colorectal Cancer ◽

Vegf Receptor ◽

Intestinal Epithelial ◽

Functional Studies

Whereas the inhibition of vascular endothelial growth factor (VEGF) has shown promising results in sporadic colon cancer, the role of VEGF signaling in colitis-associated cancer (CAC) has not been addressed. We found that, unlike sporadic colorectal cancer and control patients, patients with CAC show activated VEGFR2 on intestinal epithelial cells (IECs). We then explored the function of VEGFR2 in a murine model of colitis-associated colon cancer characterized by increased VEGFR2 expression. Epithelial cells in tumor tissue expressed VEGFR2 and responded to VEGF stimulation with augmented VEGFR2-mediated proliferation. Blockade of VEGF function via soluble decoy receptors suppressed tumor development, inhibited tumor angiogenesis, and blocked tumor cell proliferation. Functional studies revealed that chronic inflammation leads to an up-regulation of VEGFR2 on IECs. Studies in conditional STAT3 mutant mice showed that VEGFR signaling requires STAT3 to promote epithelial cell proliferation and tumor growth in vivo. Thus, VEGFR-signaling acts as a direct growth factor for tumor cells in CAC, providing a molecular link between inflammation and the development of colon cancer.

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