IFN-γ selectively exerts pro-apoptotic effects on tumor-initiating label-retaining colon cancer cells

Ni, Chao; Wu, Ping; Zhu, Xiaotao; Ye, Jun; Zhang, Zhigang; Chen, Zhigang; Zhang, Ting; Zhang, Tao; Wang, Ke; Wu, Dang; Qiu, Fuming; Huang, Jian

doi:10.1016/j.canlet.2013.04.029

Cited by 50 publications

(40 citation statements)

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“…f ). Moreover, IFN‐γ has anti‐cancer functions including cell cycle restriction, immune surveillance and pro‐apoptotic functions, and the FMT‐D group exhibited a significantly lower expression of IFN‐γ compared to the FMT‐C mice. There was no significant change in the expression of TGF‐β among the three groups (Fig.…”

Section: Resultsmentioning

confidence: 99%

Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis

et al. 2017

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The gut microbiota plays an important role in maintaining intestinal homeostasis. Dysbiosis is associated with intestinal tumorigenesis. Deoxycholic acid (DCA), a secondary bile acid increased by a western diet, correlates with intestinal carcinogenesis. However, evidence relating bile acids, intestinal microbiota and tumorigenesis are limited. In our study, we investigated the effect of DCA on induction of intestinal dysbiosis and its roles in intestinal carcinogenesis. Alteration of the composition of the intestinal microbiota was induced in DCA-treated APC mice, which was accompanied by impaired intestinal barrier, gut low grade inflammation and tumor progression. The transfer of fecal microbiota from DCA-treated mice to another group of Apc mice increased tumor multiplicity, induced inflammation and recruited M2 phenotype tumor-associated macrophages. Importantly, the fecal microbiota transplantation activated the tumor-associated Wnt/β-catenin signaling pathway. Moreover, microbiota depletion by a cocktail of antibiotics was sufficient to block DCA-induced intestinal carcinogenesis, further suggesting the role of dysbiosis in tumor development. Our study demonstrated that alteration of the microbial community induced by DCA promoted intestinal carcinogenesis.

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Section: Resultsmentioning

confidence: 99%

Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis

et al. 2017

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“…The P1and P2 cells were primary cancer cells isolated from human colon adenocarcinoma specimens obtained during surgical procedures, which was approved by the Research Ethics Board at Second Affiliated Hospital of Zhejiang University School of Medicine. The preparation of primary tumor cells was performed as described previously 4 , 31 . P1 cancer cells were cultured in RPMI-1640 (Invitrogen, Grand Island, NY) medium containing 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

Aspirin cooperates with p300 to activate the acetylation of H3K9 and promote FasL-mediated apoptosis of cancer stem-like cells in colorectal cancer

Chen

Qiu

et al. 2018

Theranostics

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Cancer stem-like cells (CSCs) have been proposed as a key driving force of tumor growth and relapse in colorectal cancer (CRC), and therefore, they are promising targets for cancer therapy. Epidemiological evidence has suggested that the daily use of aspirin reduces overall mortality of CRC and the risk of distant metastasis. We investigated the effect and mechanism of aspirin on CSCs in CRC.Methods: The ratio of CSCs was analyzed after aspirin treatment both in a cell model and patient samples. Chemically modified aspirin and immunoprecipitation were adopted to detect the target proteins of aspirin. A locus-specific light-inducible epigenetic modification system based on CRISPR technology was constructed to verify the causal relationship in these molecular events. In vivo characterization was performed in a xenograft model.Results: We found that aspirin induces apoptosis in enriched colorectal CSCs, inhibits tumor progression, and enhances the anti-neoplastic effects of chemotherapeutic agents. Furthermore, aspirin directly interacts with p300 in the nucleus, promotes H3K9 acetylation, activates FasL expression, and induces apoptosis in colorectal CSCs. Notably, these effects of aspirin are absent in non-CSCs since H3K9 is hypermethylated in non-CSCs and the effects are not induced by other NSAIDs. In addition, aspirin can suppress oxaliplatin-enriched CSCs and serve as an adjuvant therapy.Conclusions: Taken together, we revealed a unique epigenetic and cox-independent pathway (p300-AcH3K9-FasL axis) by which aspirin eliminates colorectal CSCs. These findings establish an innovative framework of the therapeutic significance of aspirin.

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“…Mouse models deficient in IFN-γ signaling display increased tumor cell proliferation [12–13]. IFN-γ was reported to selectively induce apoptosis of tumor-initiating label-retaining colon cancer cells [14]. It could alter macrophages from M2 to M1 in Apc Min/ + mouse polyps [15].…”

Section: Introductionmentioning

confidence: 99%

Lack of interferon-γ receptor results in a microenvironment favorable for intestinal tumorigenesis

et al. 2016

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IFN-γ plays an important role in innate and adaptive immunity. IFN-γ signaling is also involved in tumorigenesis, with both pro- and antitumor activities documented. We here report the characterization of intestinal tumorigenesis in ApcMin/+ mice that lack IFN-γ receptor. We observed that Ifngr1−/−ApcMin/+ mice are shorter-lived than Ifngr1+/+ApcMin/+ mice. The tumors in Ifngr1−/−ApcMin/+ mice are more likely to progress into invasive adenocarcinomas. Gene expression profiling by RNA sequencing revealed a significant upregulation of genes involved in inflammation and tissue remodeling in tumors of Ifngr1−/−ApcMin/+ mice when compared to those in Ifngr1+/+ApcMin/+ mice. In particular, five genes encoding matrix metallopeptidases (MMPs) were among the upregulated. On the other hand, genes that promote or maintain intestinal differentiation, such as Cdx2, Cdhr2 and Cdhr5, were downregulated. Tumor-associated macrophages were more abundant and were more favored toward M2 polarization in Ifngr1−/−ApcMin/+ mice than in Ifngr1+/+ApcMin/+ mice. Furthermore, the Ifngr1 was significantly downregulated in intestinal tumors when compared to mucosa. A similar trend was noted for human colorectal carcinomas. Together, our results indicate that adequate IFN-γ signaling is critical for maintaining a tumor-prohibitive microenvironment.

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IFN-γ selectively exerts pro-apoptotic effects on tumor-initiating label-retaining colon cancer cells

Cited by 50 publications

References 50 publications

Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis

Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis

Aspirin cooperates with p300 to activate the acetylation of H3K9 and promote FasL-mediated apoptosis of cancer stem-like cells in colorectal cancer

Lack of interferon-γ receptor results in a microenvironment favorable for intestinal tumorigenesis

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