Suppression of colitis-associated colorectal cancer by scutellarin through inhibiting Hedgehog signaling pathway activity

Sha Zeng; Li Tan; Qiang Sun; Li Chen; Hui Zhao; Maolun Liu; Han Yang; Shan Ren; Tianqi Ming; Shun Tang; Qiu Tao; Xianli Meng; Haibo Xu

doi:10.1016/j.phymed.2022.153972

Suppression of colitis-associated colorectal cancer by scutellarin through inhibiting Hedgehog signaling pathway activity

Phytomedicine. 2022 Apr:98:153972. doi: 10.1016/j.phymed.2022.153972. Epub 2022 Feb 4.

Authors

Sha Zeng¹, Li Tan², Qiang Sun¹, Li Chen¹, Hui Zhao¹, Maolun Liu¹, Han Yang¹, Shan Ren¹, Tianqi Ming¹, Shun Tang¹, Qiu Tao¹, Xianli Meng³, Haibo Xu⁴

Affiliations

¹ State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
² State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacy, Chongqing Medical and Health School, Chongqing 408000, China.
³ State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
⁴ State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China. Electronic address: haibo.xu@cdutcm.edu.cn.

PMID: 35151214
DOI: 10.1016/j.phymed.2022.153972

Abstract

Background: Colitis-associated colorectal cancer (CAC) is a specific type of colorectal cancer (CRC) and mainly develops from long-term intestinal inflammation. Mounting evidence reveals that activated Hedgehog signaling pathway plays a vital role in the pathogenesis of CRC. Scutellarin is a type of phytochemical flavonoid with a powerful efficacy on various malignancies, including CRC.

Aim: Here, we studied the therapeutic effect of scutellarin on CRC and its direct regulating targets.

Methods: The CAC model in mice was established by azomethane oxide (AOM) and sodium dextran sulfate (DSS), followed by detection of the efficacies of scutellarin on the carcinogenesis, apoptosis, inflammation, Hedgehog signaling cascade and complicated inflammatory networks in CAC tissues of mice. In CRC SW480 cells, the effects of scutellarin on malignant phenotype, apoptosis and Hedgehog signaling were examined. In TNF-α-stimulated IEC-6 intestinal epithelial cells, the actions of scutellarin on inflammatory response and Hedgehog signals were assessed as well.

Results: Scutellarin significantly ameliorated AOM/DSS-caused CAC in mice and induced apoptosis in CAC tissues of mice, by inhibiting NF-κB (nuclear factor kappa B) -mediated inflammation and Hedgehog signaling axis. RNA-seq and transcriptome analysis indicated that scutellarin regulated complicated inflammatory networks in mouse CAC. Also, scutellarin suppressed the proliferation, migration, colony formation, and induced apoptosis of SW480 cells by down-regulation of Hedgehog signaling pathway activity. Additionally, scutellarin lessened NF-κB-mediated inflammatory response in TNF-α-stimulated IEC-6 cells, by attenuating Hedgehog signaling cascade.

Conclusion: Scutellarin potently ameliorates CAC by suppressing Hedgehog signaling pathway activity, underpinning the promising application of scutellarin to CRC in clinical settings.

Keywords: Colitis-associated colorectal cancer; Colorectal cancer; Hedgehog signaling pathway; NF-κB signaling pathway; RNA-seq; Scutellarin.