Top

Journal of Cancer Research and Clinical Oncology

Published in:

Open Access 01-05-2024 | Colorectal Cancer | Research

Modified Lichong decoction intervenes in colorectal cancer by modulating the intestinal flora and the Wnt/β-catenin signaling pathway

Authors: Longhui Liu, Mengmeng Zhao, Xiaomeng Lang, Sujie Jia, Xin Kang, Yue Liu, Jianping Liu

Published in: Journal of Cancer Research and Clinical Oncology | Issue 5/2024

Abstract

Background

The pathogenesis and treatment of colorectal cancer (CRC) continue to be areas of ongoing research, especially the benefits of traditional Chinese medicine (TCM) in slowing the progression of CRC. This study was conducted to investigate the effectiveness and mechanism of action of modified Lichong decoction (MLCD) in inhibiting CRC progression.

Methods

We established CRC animal models using azoxymethane/dextran sodium sulfate (AOM/DSS) and administered high, medium, or low doses of MLCD or mesalazine (MS) for 9 weeks to observe MLCD alleviation of CRC. The optimal MLCD dose group was then subjected to metagenomic and RNA sequencing (RNA-seq) to explore the differentially abundant flora and genes in the control, model and MLCD groups. Finally, the mechanism of action was verified using WB, qRT‒PCR, immunohistochemistry and TUNEL staining.

Results

MLCD inhibited the progression of CRC, and the optimal effect was observed at high doses. MLCD regulated the structure and function of the intestinal flora by decreasing the abundance of harmful bacteria and increasing that of beneficial bacteria. The differentially expressed genes were mainly associated with the Wnt/β-catenin pathway and the cell cycle. Molecular biology analysis indicated that MLCD suppressed the Wnt/β-catenin pathway and the epithelial–mesenchymal transition (EMT), inhibited abnormal cell proliferation and promoted intestinal epithelial cell apoptosis.

Conclusion

MLCD mitigated the abnormal growth of intestinal epithelial cells and promoted apoptosis, thereby inhibiting the progression of CRC. This inhibition was accomplished by modifying the intestinal microbiota and disrupting the Wnt/β-catenin pathway and the EMT. Therefore, MLCD could serve as a potential component of TCM prescriptions for CRC treatment.

Aung TN, Acs B, Warrell J, Bai Y, Gaule P, Martinez-Morilla S, Vathiotis I et al (2021) A new tool for technical standardization of the Ki67 immunohistochemical assay. Mod Pathol 34(7):1261–1270. https://doi.org/10.1038/s41379-021-00745-6CrossRefPubMedPubMedCentral

Azzolin L, Panciera T, Soligo S, Enzo E, Bicciato S, Dupont S, Bresolin S et al (2014) YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. Cell 158(1):157–170. https://doi.org/10.1016/j.cell.2014.06.013CrossRefPubMed

Bennedsen ALB, Furbo S, Bjarnsholt T, Raskov H, Gögenur I, Kvich L (2022) The gut microbiota can orchestrate the signaling pathways in colorectal cancer. APMIS 130(3):121–139. https://doi.org/10.1111/apm.13206CrossRefPubMed

Brabletz T, Raghu Kalluri M, Nieto A, Weinberg RA (2018) EMT in cancer. Nat Rev Cancer 18(2):128–134. https://doi.org/10.1038/nrc.2017.118CrossRefPubMed

Brennan CA, Garrett WS (2016) Gut microbiota, inflammation, and colorectal cancer. Annu Rev Microbiol 70(1):395–411. https://doi.org/10.1146/annurev-micro-102215-095513CrossRefPubMedPubMedCentral

Choi C-HR, Ibrahim AB, Nik-Sheng D, Gui-Han L, Alan A, Janindra W, Morgan M (2019) Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study. Gut 68(3):414–22. https://doi.org/10.1136/gutjnl-2017-314190CrossRefPubMed

Fong W, Li Q, Jun Yu (2020) Gut microbiota modulation: a novel strategy for prevention and treatment of colorectal cancer. Oncogene 39(26):4925–4943. https://doi.org/10.1038/s41388-020-1341-1CrossRefPubMedPubMedCentral

Garrett WS (2019) The gut microbiota and colon cancer. Science 364(6446):1133–1135. https://doi.org/10.1126/science.aaw2367CrossRefPubMed

Gonzalez DM, Damian M (2014) Signaling mechanisms of the epithelial-mesenchymal transition. Science Signaling. https://doi.org/10.1126/scisignal.2005189CrossRefPubMedPubMedCentral

Grivennikov SI, Wang K, Daniel Mucida C, Stewart A, Schnabl B, Jauch D, Taniguchi K et al (2012) Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491(7423):254–258. https://doi.org/10.1038/nature11465CrossRefPubMedPubMedCentral

Hao H, Zhang X, Tong L, Liu Q, Liang Xi, Yushan Bu, Gong P et al (2021) Effect of extracellular vesicles derived from lactobacillus plantarum Q7 on gut microbiota and ulcerative colitis in mice. Front Immunol 12:777147. https://doi.org/10.3389/fimmu.2021.777147CrossRefPubMedPubMedCentral

He K, Gan W-J (2023) Wnt/β-catenin signaling pathway in the development and progression of colorectal cancer. Cancer Management and Research 15:435–448. https://doi.org/10.2147/CMAR.S411168CrossRefPubMedPubMedCentral

Jin S, Xianguo Wu (2019) Aspirin inhibits colon cancer cell line migration through regulating epithelial-mesenchymal transition via wnt signaling. Oncol Lett. https://doi.org/10.3892/ol.2019.10089CrossRefPubMedPubMedCentral

Krishnamurthy N, Kurzrock R (2018) Targeting the Wnt/Beta-catenin pathway in cancer: update on effectors and inhibitors. Cancer Treat Rev 62:50–60. https://doi.org/10.1016/j.ctrv.2017.11.002CrossRefPubMed

Li D, Zhang Y, Han H, Geng J, Xie X, Zheng J, Wang Y, Zou X (2012) Effect of lichong decoction on expression of IGF-I and proliferating cell nuclear antigen mRNA in rat model of uterine leiomyoma. J Tradit Chin Med 32(4):636–640. https://doi.org/10.1016/S0254-6272(13)60084-9CrossRefPubMed

Li D, Xin Xu, Qian R, Geng J, Zhang Y, Xie X, Wang Y, Zou X (2013) Effect of lichong decoction on expression of Bcl-2 and Bcl-2-associated X protein mRNAs in hysteromyoma model rat. J Tradit Chin Med 33(2):238–242. https://doi.org/10.1016/S0254-6272(13)60132-6CrossRefPubMed

Li P, Xiao Z-T, Braciak TA, Qing-Jan Ou, Chen G, Oduncu FS (2016) Association between Ki67 index and clinicopathological features in colorectal cancer. Oncol Res Treat 39(11):696–702. https://doi.org/10.1159/000450623CrossRefPubMed

Liu F, Li-Na Gu, Shan B-E, Geng C-Z, Sang M-X (2016) Biomarkers for EMT and MET in breast cancer: an update. Oncol Lett 12(6):4869–4876. https://doi.org/10.3892/ol.2016.5369CrossRefPubMedPubMedCentral

Liu C-C, Cai D-L, Sun F, Wu Z-H, Yue B, Zhao S-L, Wu X-S et al (2017) FERMT1 mediates epithelial-mesenchymal transition to promote colon cancer metastasis via modulation of β-catenin transcriptional activity. Oncogene 36(13):1779–1792. https://doi.org/10.1038/onc.2016.339CrossRefPubMed

Liu J, Chen X, Zhou X, Yi R, Yang Z, Zhao X (2021) Lactobacillus fermentum ZS09 mediates epithelial-mesenchymal transition (EMT) by regulating the transcriptional activity of the Wnt/β-catenin signalling pathway to inhibit colon cancer activity. J Inflamm Res 14:7281–7293. https://doi.org/10.2147/JIR.S344564CrossRefPubMedPubMedCentral

Ma X, Dunfang W, Xue F, Yaqing L, Jia L, Weipeng Y (2022) Huangqin tang interference with colitis associated colorectal cancer through regulation of epithelial mesenchymal transition and cell cycle. Front Pharmacol 13:837217. https://doi.org/10.3389/fphar.2022.837217CrossRefPubMedPubMedCentral

Pan W-H, Sommer F, Falk-Paulsen M, Ulas T, Best P, Fazio A, Kachroo P et al (2018) Exposure to the gut microbiota drives distinct methylome and transcriptome changes in intestinal epithelial cells during postnatal development. Genome Med 10(1):27. https://doi.org/10.1186/s13073-018-0534-5CrossRefPubMedPubMedCentral

Sebio A, Kahn M, Lenz H-J (2014) The potential of targeting Wnt/β-catenin in colon cancer. Expert Opin Ther Targets 18(6):611–615. https://doi.org/10.1517/14728222.2014.906580CrossRefPubMed

Sobhani I, Tap J, Roudot-Thoraval F, Roperch JP, Letulle S, Langella P, Corthier G, Nhieu JTV, Furet JP (2011) Microbial dysbiosis in colorectal cancer (CRC) Patients” ed. Sylviane Pied. Plos One 6(1):e16393. https://doi.org/10.1371/journal.pone.0016393CrossRefPubMedPubMedCentral

Sung, H, Jacques F, Rebecca LS, Mathieu L, Isabelle S, Ahmedin Jemal, Freddie B (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin 71(3): 209–49. https://doi.org/10.3322/caac.21660

Taddese R, Garza DR, Ruiter LN, De Jonge MI, Belzer C, Aalvink S, Nagtegaal ID, Dutilh BE, Boleij A (2020) Growth rate alterations of human colorectal cancer cells by 157 gut bacteria. Gut Microbes 12(1):1799733. https://doi.org/10.1080/19490976.2020.1799733CrossRefPubMedPubMedCentral

Vincan E, Barker N (2008) The upstream components of the wnt signalling pathway in the dynamic EMT and MET associated with colorectal cancer progression. Clin Exp Metas 25(6):657–663. https://doi.org/10.1007/s10585-008-9156-4CrossRef

Wan G, Xie M, Hongjie Yu, Chen H (2018) Intestinal dysbacteriosis activates tumor-associated macrophages to promote epithelial-mesenchymal transition of colorectal cancer. Innate Immun 24(8):480–489. https://doi.org/10.1177/1753425918801496CrossRefPubMedPubMedCentral

Wei Y, Huang C, Haoyu Wu, Huang J (2019) Estrogen receptor beta (ERβ) mediated-CyclinD1 degradation via autophagy plays an anti-proliferation role in colon cells. Int J Biol Sci 15(5):942–952. https://doi.org/10.7150/ijbs.30930CrossRefPubMedPubMedCentral

Wenna W, Zhang W, Li D, Qian R, Zhu L, Liu Y, Chen C (2020). Lichong decoction inhibits micro-angiogenesis by reducing the ex-pressions of hypoxia inducible factor-1α and vascular endothelial growth factor in hysteromyoma Mouse Model. 40(6).

Wong SH, Zhao L, Zhang X, Nakatsu G, Han J, Weiqi Xu, Xiao X et al (2017) Gavage of fecal samples from patients with colorectal cancer promotes intestinal carcinogenesis in germ-free and conventional mice. Gastroenterology 153(6):1621-1633.e6. https://doi.org/10.1053/j.gastro.2017.08.022CrossRefPubMed

Xu J, Liu D, Niu H, Zhu G, Yangwei Xu, Ye D, Li J, Zhang Q (2017) Resveratrol reverses doxorubicin resistance by inhibiting epithelial-mesenchymal transition (EMT) through modulating PTEN/Akt signaling pathway in gastric cancer. J Exp Clin Cancer Res 36(1):19. https://doi.org/10.1186/s13046-016-0487-8CrossRefPubMedPubMedCentral

Yeung KT, Yang J (2017) Epithelial–mesenchymal transition in tumor metastasis. Mol Oncol 11(1):28–39. https://doi.org/10.1002/1878-0261.12017CrossRefPubMed

Zhang M, Viennois E, Prasad M, Zhang Y, Wang L, Zhang Z, Han MK et al (2016) Edible ginger-derived nanoparticles: a novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer. Biomaterials 101:321–340. https://doi.org/10.1016/j.biomaterials.2016.06.018CrossRefPubMedPubMedCentral

Zhang N, Ng AS, Cai S, Li Q, Yang Li, Kerr D (2021) Novel therapeutic strategies: targeting epithelial-mesenchymal transition in colorectal cancer. Lancet Oncol 22(8):e358–e368. https://doi.org/10.1016/S1470-2045(21)00343-0CrossRefPubMed

Zhou He, Huang T, Xiong Y, Peng L, Wang R, Zhang GJ (2018) The prognostic value of proliferating cell nuclear antigen expression in colorectal cancer: a meta-analysis. Medicine 97(50):e13752. https://doi.org/10.1097/MD.0000000000013752CrossRefPubMedPubMedCentral

Title: Modified Lichong decoction intervenes in colorectal cancer by modulating the intestinal flora and the Wnt/β-catenin signaling pathway
Authors: Longhui Liu
Mengmeng Zhao
Xiaomeng Lang
Sujie Jia
Xin Kang
Yue Liu
Jianping Liu
Publication date: 01-05-2024
Publisher: Springer Berlin Heidelberg
Keywords: Colorectal Cancer
Colorectal Cancer
Published in: Journal of Cancer Research and Clinical Oncology / Issue 5/2024
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-024-05763-w

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 5/2024

Study on carotid artery stenosis after radiotherapy for nasopharyngeal carcinoma

Role played by MDSC in colitis-associated colorectal cancer and potential therapeutic strategies

Risk assessment model based on nucleotide metabolism-related genes highlights SLC27A2 as a potential therapeutic target in breast cancer

Primary Ewing’s sarcoma of the uterine cervix: a case report and review of the literature

GALAD score as a prognostic model for recurrence of hepatocellular carcinoma after local ablation

The emerging role and mechanism of HMGA2 in breast cancer

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials