DRO1 Inactivation Drives Colorectal Carcinogenesis in <i>ApcMin</i>/+ Mice

Grill, Jessica I.; Neumann, Jens; Herbst, Andreas; Hiltwein, Felix; Ofner, Andrea; Marschall, Maximilian K.; Wolf, Eckhard; Kirchner, Thomas; Göke, Burkhard; Schneider, Marlon R.; Kolligs, Frank T.

doi:10.1158/1541-7786.mcr-14-0205-t

Cited by 15 publications

(20 citation statements)

References 28 publications

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“…In contrast to our findings in B16 melanoma cells, CM from Apc Min/+ Dro1/Ccdc80 knockout PSC did not affect activity of caspase-3/7 in apoptosis induced intestinal epithelial cells, suggesting no modulatory role for DRO1/CCDC80 in apoptosis in the intestinal epithelium. Consistently, we have found no effect of ubiquitous inactivation of Dro1/Ccdc80 on the rate of cellular apoptosis in the intestinal epithelium and in colon tumors from Apc Min/+ mice [1]. Moreover, we could observe no influence of ubiquitous DRO1/CCDC80 loss on the apoptotic rate in carcinogen-induced colonic neoplastic lesions [6].…”

Section: Discussionsupporting

confidence: 79%

“…We found depletion of host DRO1/CCDC80 to result in c-MYC oncogenic activation in xenograft tumors, suggesting microenvironmental loss of DRO1/CCDC80 to drive carcinogenesis by c-MYC. Consistently, we demonstrated ubiquitous inactivation of Dro1/Ccdc80 to implicate increased c-MYC protein levels in the colonic epithelium and in colon tumors from Apc Min/+ mice [1]. However, treatment of RIE1 cells with CM from Dro1/Ccdc80 knockout PSC had no impact on c-MYC protein level.…”

Section: Discussionsupporting

confidence: 77%

“…Dro1/Ccdc80 has been identified as a tumor suppressor of colorectal, thyroid, and ovarian cancer [1][2][3]. Dro1/Ccdc80 suppresses anchorage independent growth [2], inhibits migration of cancer cells [4] and induces sensitization to detachment-induced apoptosis [2].…”

Section: Introductionmentioning

confidence: 99%

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Loss of DRO1/CCDC80 in the tumor microenvironment promotes carcinogenesis

et al. 2022

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Tumors are composed of the tumor cells and the surrounding microenvironment. Both are closely interwoven and interact by a complex and multifaceted cross-talk which plays an integral part in tumor initiation, growth, and progression. Dro1/ Ccdc80 has been shown to be a potent suppressor of colorectal cancer and ubiquitous inactivation of Dro1/Ccdc80 strongly promoted colorectal carcinogenesis in Apc Min/+ mice and in a chemically-induced colorectal cancer model. The aim of the present study was to investigate whether Dro1/Ccdc80's tumor suppressive function is tumor-cell-autonomous. Expression of Dro1/Ccdc80 in cancer cells had no effect on both colon tumor development in Apc Min/+ mice and formation of xenograft tumors. In contrast, DRO1/CCDC80 loss in the microenvironment strongly increased tumor growth in xenograft models, inhibited cancer cell apoptosis, and promoted intestinal epithelial cell migration. Moreover, stromal Dro1/Ccdc80 inactivation facilitated formation of intestinal epithelial organoids. Expression analyses showed Dro1/Ccdc80 to be significantly down-regulated in murine gastric cancer associated fibroblasts, in Apc Min/+ colon tumor primary stromal cells and in microdissected stroma from human colorectal cancer compared to normal, non-tumor stroma. Our results demonstrate epithelial derived DRO1/CCDC80 to be dispensable for intestinal tissue homeostasis and identify Dro1/Ccdc80 as tumor suppressor in the tumor microenvironment.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 77%

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Loss of DRO1/CCDC80 in the tumor microenvironment promotes carcinogenesis

et al. 2022

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“…CCDC80, also known as downregulated by oncogenes 1 (DRO1), is shown to be downregulated in many types of cancers, including CRC, pancreatic cancer, and thyroid cancer (Visconti et al, 2003;Bommer et al, 2005). Loss of CCDC80 increased the development of carcinoma in ApcMin/− mice, suggesting that CCDC80 acts as a tumor suppressor in colon tumorigenesis (Grill et al, 2014). In our data, overexpression of CCDC80 significantly suppressed CRC cell proliferation and tumor growth and induced the expression of c-MYC.…”

Section: Discussionsupporting

confidence: 55%

Coiled-Coil Domain Containing 80 Suppresses Nonylphenol-Induced Colorectal Cancer Cell Proliferation by Inhibiting the Activation of ERK1/2

Wang

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Recently, the effect of endocrine-disrupting chemicals on the cancer procession has been a concern. Nonylphenol (NP) is a common environmental estrogen that has been shown to enhance the proliferation of colorectal cancer (CRC) cells in our previous studies; however, the underlying mechanism remains unclear. In this study, we confirmed the increased concentration of NP in the serum of patients with CRC. RNA sequencing was used to explore the differentially expressed genes after NP exposure. We found 16 upregulated genes and 12 downregulated genes in COLO205 cells after NP treatment. Among these differentially expressed genes, we found that coiled-coil domain containing 80 (CCDC80) was downregulated by NP treatment and was associated with CRC progression. Further experiments revealed that the overexpression of CCDC80 significantly suppressed NP-induced cell proliferation and recovered the reduced cell apoptosis. Meanwhile, the overexpression of CCDC80 significantly inhibited the activation of ERK1/2 induced by NP treatment. ERK1/2 inhibitor (PD98059) treatment also suppressed NP-induced CRC cell growth, but the overexpression of CCDC80 did not enhance the effect of ERK1/2 inhibitor. Taken together, NP treatment significantly inhibited the expression of CCDC80, and the overexpression of CCDC80 suppressed NP-induced CRC cell growth by inhibiting the activation of ERK1/2. These results suggest that NP could induce CRC cell growth by influencing the expression of multiple genes. CCDC80 and ERK1/2 inhibitors may be suitable therapeutic targets in NP-related CRC progression.

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“…For this reason, the statistical power to study the colonic region in these rat models exceeds that of the Apc Min/+ mouse. Although colonic tumorigenesis can be increased in mouse models, it requires further genetic manipulation, carcinogenic treatments, or chemical or physical abrasion ( Byun et al, 2014 ; Grill et al, 2014 ; Hinoi et al, 2007 ; Hung et al, 2010 ; Møllersen et al, 2004 ; Paul Olson et al, 2014 ; Ritchie et al, 2009 ; Suzui et al, 2002 ).…”

Section: Rodent Models Of Colon Cancermentioning

confidence: 99%

The utility of Apc-mutant rats in modeling human colon cancer

Irving

Yoshimi

Hart

et al. 2014

Disease Models &Amp; Mechanisms

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Prior to the advent of genetic engineering in the mouse, the rat was the model of choice for investigating the etiology of cancer. Now, recent advances in the manipulation of the rat genome, combined with a growing recognition of the physiological differences between mice and rats, have reignited interest in the rat as a model of human cancer. Two recently developed rat models, the polyposis in the rat colon (Pirc) and Kyoto Apc Delta (KAD) strains, each carry mutations in the intestinal-cancer-associated adenomatous polyposis coli (Apc) gene. In contrast to mouse models carrying Apc mutations, in which cancers develop mainly in the small intestine rather than in the colon and there is no gender bias, these rat models exhibit colonic predisposition and gender-specific susceptibility, as seen in human colon cancer. The rat also provides other experimental resources as a model organism that are not provided by the mouse: the structure of its chromosomes facilitates the analysis of genomic events, the size of its colon permits longitudinal analysis of tumor growth, and the size of biological samples from the animal facilitates multiplexed molecular analyses of the tumor and its host. Thus, the underlying biology and experimental resources of these rat models provide important avenues for investigation. We anticipate that advances in disease modeling in the rat will synergize with resources that are being developed in the mouse to provide a deeper understanding of human colon cancer.

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DRO1 Inactivation Drives Colorectal Carcinogenesis in ApcMin/+ Mice

Cited by 15 publications

References 28 publications

Loss of DRO1/CCDC80 in the tumor microenvironment promotes carcinogenesis

Loss of DRO1/CCDC80 in the tumor microenvironment promotes carcinogenesis

Coiled-Coil Domain Containing 80 Suppresses Nonylphenol-Induced Colorectal Cancer Cell Proliferation by Inhibiting the Activation of ERK1/2

The utility of Apc-mutant rats in modeling human colon cancer

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