GNAI1 and GNAI3 Reduce Colitis-Associated Tumorigenesis in Mice by Blocking IL6 Signaling and Down-regulating Expression of GNAI2

Li, Zhi Wei; Sun, Beicheng; Gong, Ting; Guo, Shouwu; Zhang, Jianhua; Wang, Junlong; Sugawara, Atsushi; Jiang, Meisheng; Yan, Junjun; Gurary, Alexandra; Zheng, Xin Xiao; Gao, Bifeng; Xiao, Shu Yuan; Chen, Wenlian; Ma, Chi; Farrar, Christine; Zhu, Chenjun; Chan, Owen; Xin, Can; Winnicki, Andrew; Winnicki, John; Tang, Mingxin; Park, Ryan M.; Winnicki, Mary; Diener, Katrina; Wang, Zhanwei; Liu, Qicai; Chu, Catherine; Arter, Zhaohui; Yue, Peibin; Alpert, Lindsay; Hui, George; Fei, Peiwen; Turkson, James; Yang, Wentian; Wu, Guangyu; Tao, Ailin; Ramos, Joe W.; Moisyadi, Stefan; Holcombe, Randall F.; Wang, Jia; Birnbaumer, Lutz; Zhou, Xiqiao; Chu, Weihua

doi:10.1053/j.gastro.2019.02.040

Cited by 64 publications

(51 citation statements)

References 49 publications

(58 reference statements)

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“…Some studies showed TRAF6 could be recruited to other signaling pathways (IL-1, IL-6, IL-8 and LPS) as a very important adapter protein to activate the NF-κB/c-jun signaling pathway. [34][35][36] In our previous study, we also found…”

Section: Discussionmentioning

confidence: 53%

The Effects of TRAF6 on Growth and Progression in Colorectal Cancer are Regulated by miRNA-140

Zhu¹,

Cheng²,

Lin³

et al. 2020

OTT

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Background and Aim: Some studies have confirmed that miRNA-140 exhibits a suppressive role in gastric cancer, Wilms' tumor. However, the function of miRNA-140 in colorectal cancer has not been completely elucidated. The present study aims to verify TRAF6 as the targeted gene by miRNA-140 which was investigated in colorectal cancer tissues and cells, and its effects on the biological characteristics of colorectal cancer cells were determined, in order to provide an experimental and theoretical basis for the application of TRAF6 in the treatment of colorectal cancer. Methods: qPCR analyzed miRNA-140 expression levels in colorectal cancer tissues, normal colorectal cancer tissues and colorectal cells including SW480 and HCT116 cancer cells and FHC normal colorectal epithetical cells. A serial biological experiment analyzed miRNA-140 effects on cell proliferation, migration and invasion capacities in SW480 and HCT116 cells. miRNA targeting gene prediction and a dual luciferase assay were used to analyze miRNA-140-targeted TRAF6. qPCR and Western blot analyzed miRNA-140 effects on the mRNA and protein expression of TRAF6. Western blot analyzed miRNA-140 effects on NF-κB/c-jun signaling pathways. Animal studies were performed to investigate the effects of miRNA-140 on colorectal cancer implantation tumor growth. Immunohistochemistry analyzed TRAF6 expression in animal experimentation tumors. Results: miRNA-140 expression is lower in colorectal cancer tissues and colorectal cancer cells. Over-expression of miRNA-140 inhibited the proliferation, migration and invasion capacities of colorectal cancer cells. miRNA-140 targeted the TRAF6 mRNA 3ʹUTR area and decreased TRAF6 protein expression. miRNA-140 suppressed p-NF-κB/p-c-jun proteins expression. miRNA-140 inhibited colorectal cancer implantation tumor growth in the mice model. Conclusion: miRNA-140 targeting TRAF6 affects the progression and growth of colorectal cancer, the mechanism could be miRNA-140 decreasing the TRAF6 expression effects on the NF-κB/c-jun signaling pathways.

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Section: Discussionmentioning

confidence: 53%

The Effects of TRAF6 on Growth and Progression in Colorectal Cancer are Regulated by miRNA-140

Zhu¹,

Cheng²,

Lin³

et al. 2020

OTT

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“…The present study shows that TRAF6 promotes CRC progression. TRAF6 is involved in inflammation signaling pathways (IL-1, IL-8, IL-6 and LPS), which provide crucial adapter proteins to activate the nuclear factor kappa-light-chainenhancer of activated B (NF-ĸB) cells and activator protein 1 (AP-1) pathways (33)(34)(35). Sun et al, (36) have shown that TRAF6 promotes colon cancer-cell proliferation and could be a potential target for colon cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

TRAF6-Mediated Inflammatory Cytokines Secretion in LPS-induced Colorectal Cancer Cells Is Regulated by miR-140

Zhu

Lin

Cheng

et al. 2019

Cancer Genomics Proteomics

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Background/Aim: Colorectal cancer (CRC) cells secrete inflammatory cytokines that affect CRC progression. The aim of the present study was to determine if micro-RNA-140(miR-140) regulates inflammatory cytokine secretion induced by lipopolysaccharide (LPS) in colorectal cancer cells by targeting tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). Materials and Methods: Fifty fresh coloncancer specimens and normal colorectal tissues were collected from patients with CRC and tested for the expression miR-140. Human CRC cell lines SW480 and HCT116 were treated with various concentrations and times with LPS. miR-140 and mRNA expression of potentially related genes were analyzed by qPCR. Protein expression was analyzed using western blot or ELISA. Overexpression plasmids with pcDNA3.1-TRAF6, pGL4.10-wtTRAF6 and pGL4.10-mutTRAF6 were constructed. miRNA target gene prediction and a dual luciferase assay were used to analyze miR-140-targeted TRAF6. Results: miR-140 expression was up-regulated in CRC tissues. In CRC cells, LPS could increase miR-140 expression in a time-and concentration-dependent manner. LPS increased inflammatory cytokine mRNA expression levels in SW480 and HCT116 human colon-cancer cells. miRNA-140 suppressed TRAF6 expression via targeting the 3΄UTR. TRAF6 affected miR-140-mediated inflammatory cytokine expression of SW480 and HCT116 cells under LPS treatment. Conclusion: miR-140 regulates inflammatory cytokine secretion of LPS-induced colorectal cancer cells by targeting TRAF6. Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States and the third most common cause of cancer death (1). It is estimated that globally more than 2.2 million new cases and 1.1 million deaths will occur by 2030 due to CRC (2). The coexistence of inflammation and cancer has been known for a long time. Inflammation may promote cancer progression (3-5). CRC cells can secrete inflammatory cytokines which play an important role in CRC development (6, 7), however, the mechanisms by which inflammation can promote cancer progression are poorly understood. MicroRNAs (miRNAs) are small, single stranded, noncoding RNAs consisting of 20-22 nucleotides, which play significant roles in many biological process by regulating gene expression at the post-transcriptional level (8). The mechanism by which miRNAs work is by binding to the complementary sites in the 3΄ untranslated region (3΄UTR) of the target genes, which induces degradation of the mRNA transcripts or translational repression (9). miRNAs are involved in many physiological processes, including cell proliferation, apoptosis, cell cycle and cell differentiation (10, 11). More and more evidence indicates that miRNAs are involved in the regulation of cancer-related genes (12-14), as well as of inflammatory cytokine secretion by CRC cells (15-17).

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“…In the progression of CRC, the regulation of each stage of the tumour can be accomplished through these molecular pathways. For example, a study proved that the NF-κB-IL6-STAT3 pathway promoted CRC [72]. The activation of the IL-6/STAT3/ERK signaling pathway facilitates the angiogenesis, migration and proliferation of CRC.…”

Section: Il-6mentioning

confidence: 99%

The Role of Interleukins in Colorectal Cancer

Huang

Zhao

et al. 2020

Int. J. Biol. Sci.

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Despite great progress has been made in treatment strategies, colorectal cancer (CRC) remains the predominant life-threatening malignancy with the feature of high morbidity and mortality. It has been widely acknowledged that the dysfunction of immune system, including aberrantly expressed cytokines, is strongly correlated with the pathogenesis and progression of colorectal cancer. As one of the most well-known cytokines that were discovered centuries ago, interleukins are now uncovering new insights into colorectal cancer therapy. Herein, we divide currently known interleukins into 6 families, including IL-1 family, IL-2 family, IL-6 family, IL-8 family, IL-10 family and IL-17 family. In addition, we comprehensively reviewed the oncogenic or antitumour function of each interleukin involved in CRC pathogenesis and progression by elucidating the underlying mechanisms. Furthermore, by providing interleukins-associated clinical trials, we have further driven the profound prospect of interleukins in the treatment of colorectal cancer.

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GNAI1 and GNAI3 Reduce Colitis-Associated Tumorigenesis in Mice by Blocking IL6 Signaling and Down-regulating Expression of GNAI2

Abstract: Author contributions: Wen-Ming Chu conceived and directed the project and performed a large body of experiments.

Cited by 64 publications

References 49 publications

<p>The Effects of <em>TRAF6</em> on Growth and Progression in Colorectal Cancer are Regulated by <em>miRNA-140</em></p>

<p>The Effects of <em>TRAF6</em> on Growth and Progression in Colorectal Cancer are Regulated by <em>miRNA-140</em></p>

TRAF6-Mediated Inflammatory Cytokines Secretion in LPS-induced Colorectal Cancer Cells Is Regulated by miR-140

The Role of Interleukins in Colorectal Cancer

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