SIX4 Activation in Inflammatory Response Drives the Transformation of Colorectal Epithelium into Inflammation and Tumor via Feedback-Enhancing Inflammatory Signaling to Induce Tumor Stemness Signaling

Zhang, Ziyan1,2,3; Huang, Huang4; Peng, Lanzhu1; Zhou, Beixian5; Yang, Huiling6; Tang, Zibo1,7; Yan, Weiwei1; Chen, Weifeng1; Liu, Zhen8; Zheng, Dayong9,10; Shen, Peng11; Fang, Weiyi1,3

2024

10.7150/ijbs.93411

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES   影响因子和分区

1449-2288

Some colorectal cancer patients have experienced normal epithelial transformation into inflammatory and tumor states, but the molecular basis still needs to be further determined. The expression levels of SIX4 are gradually increased in dextran sodium sulfate (DSS) and azoxymethane (AOM)/DSS-induced colonic epithelial inflammation and tumors, respectively, in mice. Targeting SIX4 alleviates intestinal inflammation occurrence and reduces adenoma formation in mice. Clinical sample assays indicated that SIX4 is upregulated in inflammatory bowel disease (IBD) and colorectal cancer (CRC) tissues compared to normal colorectal tissues. In a subsequent study, we found that SIX4, transcriptionally activated by the proinflammatory IL-6/STAT3 signal, binds to c-Jun to transcribe IL-6, thus forming a positive IL-6/STAT3/SIX4/c-Jun feedback loop, which further induces intestinal inflammation occurrence. In addition, elevated SIX4 also induces the expression of DeltaNp63, rather than wild-type p63, by binding to its promoter and thus facilitates the activation of tumor stemness signals, which ultimately leads to the formation of colorectal cancer. Our study first observes that activated SIX4 in inflammation induction drives the transformation of colorectal epithelium into inflammation and tumor, which demonstrates SIX4 as a significant therapeutic target in IBD and colitis-associated colorectal cancer (CAC) and CRC pathogenesis.

SCI

英语

其他

Science and Technology Program of Guangzhou City[202206010068] ; Guangdong Basic and Applied Basic Research Foundation["2021A1515012430","2023A1515111009"] ; Foundation of President of Nanfang Hospital, Southern Medical University[2023A017] ; Postdoctoral Fellowship Program of CPSF[GZC20242077]

Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics

Biochemistry & Molecular Biology ; Biology

WOS:001309543000003

IVYSPRING INT PUBL

Web of Science

1.Southern Med Univ, Integrated Hosp Tradit Chinese Med, Canc Ctr, Guangzhou 510315, Peoples R China
2.Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Radiotherapy, Guangzhou 528406, Peoples R China
3.Southern Med Univ, Affiliated Hosp 3, Dept Gynecol & Obstet, Guangzhou 510630, Peoples R China
4.Southern Med Univ, Nanfang Hosp, Nursing Dept, Guangzhou 510516, Peoples R China
5.Peoples Hosp Gaozhou, Gaozhou 525200, Peoples R China
6.Guangdong Med Univ, Sch Pharm, Dongguan 523808, Peoples R China
7.Southern Univ Sci & Technol, Jinan Univ, Shenzhen Peoples Hosp, Affiliated Hosp 1,Clin Med Coll 2,Dept Radiat Onco, Shenzhen 518020, Peoples R China
8.Guangzhou Med Univ, Sch Basic Med Sci, Guangzhou Municipal & Guangdong Prov Key Lab Prot, Guangzhou 510095, Guangdong, Peoples R China
9.South Med Univ, Shunde Hosp, Foshan, Guangdong, Peoples R China
10.Kashi First Peoples Hosp, Kashi 844099, Peoples R China
11.Nanfang Hosp Southern Med Univ, Dept Oncol, Guangzhou 510515, Peoples R China

Zhang, Ziyan,Huang, Huang,Peng, Lanzhu,et al. SIX4 Activation in Inflammatory Response Drives the Transformation of Colorectal Epithelium into Inflammation and Tumor via Feedback-Enhancing Inflammatory Signaling to Induce Tumor Stemness Signaling[J]. INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES,2024,20(12).

Zhang, Ziyan.,Huang, Huang.,Peng, Lanzhu.,Zhou, Beixian.,Yang, Huiling.,...&Fang, Weiyi.(2024).SIX4 Activation in Inflammatory Response Drives the Transformation of Colorectal Epithelium into Inflammation and Tumor via Feedback-Enhancing Inflammatory Signaling to Induce Tumor Stemness Signaling.INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES,20(12).

Zhang, Ziyan,et al."SIX4 Activation in Inflammatory Response Drives the Transformation of Colorectal Epithelium into Inflammation and Tumor via Feedback-Enhancing Inflammatory Signaling to Induce Tumor Stemness Signaling".INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES 20.12(2024).