BMI1 and MEL18 Promote Colitis-Associated Cancer in Mice via REG3B and STAT3

Liu, Xi-Cheng; Wei, Wendi; Li, Xiaowei; Shen, Pengcheng; Ju, Dapeng; Wang, Zhen; Zhang, Rukui; Fu, Yang; Chen, Chunyan; Cao, Kun; Zhu, Guoli; Chen, Hongyan; Chen, Liang; Sui, Jianhua; Zhang, Erquan; Wu, Kaichun; Wang, Fengchao; Zhao, Liping; Xi, Rongwen

doi:10.1053/j.gastro.2017.07.044

Cited by 51 publications

(51 citation statements)

References 43 publications

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“…2j). Notably, starting 3 months PTI, acinar cells expressed high levels of Reg genes, including Reg3b, that inhibits the Stat3 signaling pathway 25 . In addition, late acinar cells express the S100a family genes, immune-related genes, such as C4b and Cd74, and the ductal marker Krt19 ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity

Schlesinger¹,

Yosefov-Levi²,

et al. 2020

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Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.

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Section: Resultsmentioning

confidence: 99%

Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity

Schlesinger¹,

Yosefov-Levi²,

et al. 2020

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“…The initiation of inflammation is often accompanied by the induction of certain proinflammatory cytokines such as IL‐1β, IL‐6 and TNF‐α . Given that these proinflammatory cytokines have been reported to be up‐regulated in patients with CAC , we examined their levels in our samples. In agreement with the other publications, we found that these proinflammatory cytokines were significantly up‐regulated, and their levels positively correlated with TNM stages (Figure ), suggesting that these proinflammatory cytokines were not only critical for the tumour initiation but also important for tumour metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…The activation of proinflammatory pathways such as the NF‐κB and cytokine (e.g. TNF‐α and IL‐6)‐dependent signalling creates a proinflammatory microenvironment, which may initiate CAC . Besides NF‐κB, another transcription factor, c‐Myc, is overexpressed in CRC and controls cell growth, proliferation and differentiation .…”

Section: Introductionmentioning

confidence: 99%

Inflammation‐dependent overexpression of c‐Myc enhances CRL4^DCAF4 E3 ligase activity and promotes ubiquitination of ST7 in colitis‐associated cancer

Liu

et al. 2019

The Journal of Pathology

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Inflammation is well known as an important driver of the initiation of colitis-associated cancer (CAC). Some cytokines, such as IL-6 and TNF- can activate expression of the oncogene c-Myc (MYC) and regulate its downstream effects. Cullin-RING E3 Ligases (CRLs) are emerging as master regulators controlling tumorigenesis.Here, we demonstrate that two cullin genes, CUL4A and CUL4B, but not other members, are specifically overexpressed in CAC tumour samples and positively correlate with levels of the proinflammatory cytokines IL-1 and IL-6. In vitro experiments revealed that the transcription factor c-Myc can specifically activate the expression of CUL4A and CUL4B by binding to a conserved site (CACGTG) located in their promoters. Additionally, we found that both CUL4A and CUL4B can form an E3 complex with DNA damage-binding protein 1 (DDB1) and DDB1-CUL4-associated factor 4 (DCAF4). In vitro and in vivo ubiquitination analyses indicate that CRL4 DCAF4 E3 ligase specifically directs degradation of ST7 (suppression of tumorigenicity 7). Overexpression of c-Myc in human colon epithelial cells resulted in the accumulation of CUL4A, CUL4B and DCAF4, but degradation of ST7. In contrast, knockdown of c-Myc, CUL4A or CUL4B in the colon adenocarcinoma cell line HT29 caused accumulation of ST7 and inhibition of cell proliferation, colony formation ability and in vivo tumour growth. Collectively, our results provide in vitro and in vivo evidence that c-Myc regulates CRL4 DCAF4 E3 ligase activity to mediate ubiquitination of ST7, whose presence is physiologically essential for CAC tumorigenesis.No conflicts of interest were declared. ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s) [16,17]. The human genome encodes two E1s, ∼40 E2s and more than 600 E3s [18,19]. Of these E3 ligases, Cullin-RING

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“…In addition, the activation of STAT3 can upregulate anti-apoptosis genes to inhibit cell apoptosis ( 20 , 21 ). It was reported that some extracts or genes promoted cell apoptosis and inhibited cell migration and invasion and caused cycle arrest in kidney, breast, ovarian and colon cancer by inhibiting the activation of STAT3 ( 16 , 36 – 39 ). Therefore, the phosphorylation levels of JAK2 and STAT3 were further determined in cells transfected with RPN2 siRNA.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of RPN2 induces apoptosis and inhibits migration and invasion in colon carcinoma

Jiang

2018

Oncol Rep

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The morbidity of colorectal cancer (CRC) increases annualy, which accounts to higher mortality worldwide. Therefore, it is important to study the pathogenesis of colon cancer. Ribophorin II (RPN2), part of the N-oligosaccharyltransferase complex, is highly expressed in CRC. In the present study, we investigated whether RPN2 can regulate apoptosis, migration and invasion by RNA interference in CRC and sought to clarify the molecular mechanism involved. Based on previous research, an abnormal high expression of RPN2 was observed in CRC tissues and cell lines by real-time (RT)-PCR, immunohistochemistry (IHC) and western blot analysis. RPN2 knockdown via small RNA interference (siRNA) strategy attenuated the expression of RPN2 at the mRNA and protein levels in vivo, leading to decreased cell viability and increased cell apoptosis. In addition, RNAi-RPN2 effectively arrested the cell cycle at the G0/G1-phase in SW1116 and SW480 cells. Furthermore, the Transwell assay demonstrated that cell migration and invasion abilities were significantly inhibited after cell transfection with RPN2 interference plasmid. The apoptosis-related protein (caspase-3) expression was increased and the cell cycle-related protein (cyclin D1) expression was decreased in the siRNA-RPN2 group. RT-PCR and western blot analysis results indicated that migration- and invasion-related proteins including E-cadherin, matrix metalloproteinases (MMP)-2 and TIMP-2 were markedly regulated by RPN2 siRNA. Phosphorylation levels of signal transducer and activator of transcription (STAT)3 and Janus kinase (JAK)2 were inhibited by RPN2 siRNA. These findings indicated a novel pathway of tumor-promoting activity by RPN2 in CRC, with significant implications for unraveling the tumorigenesis of CRC.

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BMI1 and MEL18 Promote Colitis-Associated Cancer in Mice via REG3B and STAT3

Cited by 51 publications

References 43 publications

Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity

Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity

Inflammation‐dependent overexpression of c‐Myc enhances CRL4^DCAF4 E3 ligase activity and promotes ubiquitination of ST7 in colitis‐associated cancer

Downregulation of RPN2 induces apoptosis and inhibits migration and invasion in colon carcinoma

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BMI1 and MEL18 Promote Colitis-Associated Cancer in Mice via REG3B and STAT3

Cited by 51 publications

References 43 publications

Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity

Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity

Inflammation‐dependent overexpression of c‐Myc enhances CRL4DCAF4 E3 ligase activity and promotes ubiquitination of ST7 in colitis‐associated cancer

Downregulation of RPN2 induces apoptosis and inhibits migration and invasion in colon carcinoma

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Inflammation‐dependent overexpression of c‐Myc enhances CRL4^DCAF4 E3 ligase activity and promotes ubiquitination of ST7 in colitis‐associated cancer