Atonal homolog 1 protein stabilized by tumor necrosis factor α induces high malignant potential in colon cancer cell line

Fukushima, Kunihiro; Tsuchiya, Kiichiro; Kano, Yoshihito; Horita, Nobukatsu; Hibiya, Shuji; Hayashi, Ryohei; Kitagaki, Keisuke; Negi, Mariko; Itoh, Eiichi; Akashi, Takumi; Eishi, Yoshinobu; Nagaishi, Takashi; Okamoto, Ryuichi; Nakamura, Toshio; Watanabe, Mamoru

doi:10.1111/cas.12703

Cited by 20 publications

(20 citation statements)

References 27 publications

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“…Depending on the cellular context, ATOH1, also known as Math1 and Hath1, may function both as an oncogene, for example, in medulloblastoma (Briggs et al, 2008;Grausam et al, 2017) or as a tumor suppressor gene, for example, in colon (Bossuyt et al, 2009;Fukushima et al, 2015), gastric (Han et al, 2015), and hepatocellular cancer (Gao et al, 2017). Despite its high expression in MCC tissues and in classical MCC cell lines (Gambichler et al, 2017), knockdown of ATOH1 did not affect cell viability or proliferation of MCC cells.…”

Section: Discussionmentioning

confidence: 99%

MCPyV Large T Antigen-Induced Atonal Homolog 1 Is a Lineage-Dependency Oncogene in Merkel Cell Carcinoma

Fan

Gravemeyer

Ritter

et al. 2020

Journal of Investigative Dermatology

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Despite the fact that the transcription factor ATOH1 is a master regulator of Merkel cell development, its role in Merkel cell carcinoma (MCC) carcinogenesis remains controversial. Here, we provide several lines of evidence that ATOH1 is a lineage-dependent oncogene in MCC. Luciferase assays revealed binding of ATOH1 and subsequent activation to the promoter of miR-375, which is one of the most abundant microRNAs in MCCs. Overexpression of ATOH1 in variant MCC cell lines and fibroblasts induced miR-375 expression, whereas ATOH1 knockdown in classical MCC cell lines reduced miR-375 expression. Moreover, ATOH1 overexpression in these cells changed their growth characteristics from adherent to suspension and/orspheroidal growth, that is, resembling the neuroendocrine growth pattern of classical MCC cell lines. Notably, ectopic expression of different Merkel cell polyomavirus (MCPyV)-derived truncated large T antigens induced ATOH1 expression in fibroblasts, which was paralleled by miR-375 expression and similar morphologic changes. In summary, MCPyVassociated carcinogenesis is likely to induce the characteristic neuroendocrine features of MCC via induction of ATOH1; thus, ATOH1 can be regarded as a lineage-dependent oncogene in MCC.

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Section: Discussionmentioning

confidence: 99%

MCPyV Large T Antigen-Induced Atonal Homolog 1 Is a Lineage-Dependency Oncogene in Merkel Cell Carcinoma

Fan

Gravemeyer

Ritter

et al. 2020

Journal of Investigative Dermatology

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“…IECspecific deletion of IKKb, a key molecule in the NF-jB pathway, reduced the incidence of colitis-induced tumorigenesis, suggesting that IEC-intrinsic NF-jB activation is a major regulator of CAC [88]. Recent studies have suggested that TNF-a may also induce constitutive expression of the transcription factor ATOH1, and direct tumor cells to acquire highly proliferative, and invasive character [89,90]. Also, loss of the gp130-STAT3 axis in IECs reduces the growth and multiplicity of colitis-induced tumors [91].…”

Section: Colitis-associated Cancer Represents Another Aspect Of Iec-dmentioning

confidence: 99%

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

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In the past decades, continuous effort has been paid to deeply understanding the pathophysiology of inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohn's disease. As the disease typically arises as chronic inflammation of the gastrointestinal mucosa, research has been focused on how such an uncontrolled, deleterious immune response may arise and persist in a certain cohort of patients. Based on those immunologic analyses, the establishment of anti-TNF-a therapy, and the following series of biologic agents achieved great success and dramatically changed the therapeutic strategy of IBD patients. However, to guarantee long-term remission of the disease, the therapeutic standard has been raised to achieve ''mucosal healing'', which requires complete repair of the gastrointestinal mucosa. Recent studies have revealed the unexpected importance of epithelial cells in the pathophysiology of IBD. The general barrier function as well as the cell lineage-specific functions have been deeply attributed to the development of chronic intestinal inflammation. Also, the groundbreaking establishment of the in vitro intestinal stem cell culture system has opened up a way of developing stem cell transplantation therapy to treat otherwise refractory ulcers that may persist in IBD patients. In this review, we would like to focus on the role of epithelial cells in the pathophysiology of IBD, and also give a perspective to the upcoming development of regenerative therapies that may become one of the therapeutic choices to achieve mucosal healing in refractory patients of IBD.

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“…The lentivirus generated from Lenti-CRISPR v2 vector with target array were infected to LS174T cells as described previously (11). As a negative control, LS174T TP53WT cells were generated by infection with the Lenti-CRISPR v2 vector lacking the target array such that these cells would also constitutively express Cas9.…”

Section: Crispr-cas9-mediated Mutagenesismentioning

confidence: 99%

“…Total RNA was isolated using an RNeasy Micro Kit (Qiagen) according to the manufacturer's instructions. cDNA synthesis was performed as described previously (11). One microliter of cDNA was amplified using a QuantiTect SYBR Green PCR Kit (Qiagen) in a reaction volume of 20 mL.…”

Section: Qrt-pcrmentioning

confidence: 99%

TP53 Mutation by CRISPR System Enhances the Malignant Potential of Colon Cancer

Watanabe

Tsuchiya

Nishimura

et al. 2019

Molecular Cancer Research

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Tumor protein p53 (TP53) mutation is a well-known occurrence at the late phase of carcinogenesis during the adenoma-carcinoma sequence of a sporadic colon cancer. Although numerous reports about clinical information of the patients with colon cancer have suggested that TP53 mutation might be related to various types of malignant potential, the direct effects of this mutation on the malignant potential of colon cancer remain unknown. Notably, no previous report has described a relationship between TP53 mutation and cancer stemness. We therefore aimed to assess the function of a TP53 mutant induced by the CRISPR-Cas9 system in colon cancer cells. In this study, two TP53 mutations, corresponding to exon 3 (TP53E3) and 10 (TP53E10), were generated in LS174T cells derived from a wild-type TP53 human colon cancer via a lentiviral CRISPR-Cas9 system. The loss of function of TP53 resulting from both mutations manifested as resistance to Nutlin3a-induced apoptosis and the downregulation of target genes of TP53. TP53 mutants exhibited an enhanced malignant potential, characterized by accelerated cell growth, invasiveness, chemoresistance, and cancer stemness. Interestingly, TP53E10 but not TP53E3 cells exhibited aberrant transcriptional activity of regenerating family member 1-a (REG1A) and expression of REG1A, resulting in the acquisition of enhanced malignant potential. In conclusion, we demonstrated for the first time that TP53 genomic mutation into human colon cancer cells affects the malignant potential. Implications: These findings suggest that both a loss of function and an aberrant gain of function of TP53 might promote high malignant potentials at the late phase of carcinogenesis in colon cancer.

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Atonal homolog 1 protein stabilized by tumor necrosis factor α induces high malignant potential in colon cancer cell line

Cited by 20 publications

References 27 publications

MCPyV Large T Antigen-Induced Atonal Homolog 1 Is a Lineage-Dependency Oncogene in Merkel Cell Carcinoma

MCPyV Large T Antigen-Induced Atonal Homolog 1 Is a Lineage-Dependency Oncogene in Merkel Cell Carcinoma

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

TP53 Mutation by CRISPR System Enhances the Malignant Potential of Colon Cancer

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