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Bacterial metabolite butyrate in modulating sorafenib-targeted microRNAs to curtail its resistance in hepatocellular carcinoma

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Abstract

Background and Aim

The host dietary fibre is fermented into short-chain fatty acids (SCFA) by intestinal microbiota as bacterial metabolites like propionate, acetate and butyrate. Among these metabolites, the role of butyrate is well documented to provide energy to intestinal epithelial cells. Also, butyrate has anti-inflammatory and anti-tumour properties and decrease in its level by unbalanced diet can develops cancer. Lately, some research has suggested that sodium butyrate as an inhibitor of histone deacetylase (HDAC) may have anticancer potential for hepatocellular carcinoma (HCC), the most common type of liver cancer. Since, HCC is asymptomatic it is usually diagnosed at its advanced stage. Sorafenib with antiproliferative and antiangiogenic effects is the first line of treatment in advanced HCC. However, prolonged drug treatment to HCC patients develops adaptive resistance towards the sorafenib. Sorafenib resistance can also be enhanced by differentially expressed microRNAs. However, the significance of butyrate in HCC sorafenib resistance and its association with sorafenib-targeted microRNAs is yet to be unfurled. Here, an attempt has been made to explore the role of bacterial metabolite butyrate on sorafenib resistant HCC as well as on sorafenib-targeted microRNAs (miR-7641 and miR-199) to curtail sorafenib resistance in HCC.

Methods

Initially, in-silico analysis was performed using Human Metabolome Database (HMDB) so to identify specific butyrate producing faecal bacteria. Then, their specific 16s rRNA expression was compared between HCC patients and healthy individuals using qRT-PCR. Additionally, the cell viability (MTT) and apoptosis assays were performed in both parental and sorafenib resistant HepG2 cells to evaluate the role of sodium butyrate in sorafenib resistant HCC. Moreover, the association of sodium butyrate with sorafenib-targeted miR-7641 and miR-199 was also assessed using real time PCR, cell viability, cell apoptosis and transfection assays.

Results

In silico analysis demonstrated Roseburia cecical, Roseburia intestinalis, Eubacterium rectal, Faecalibacterium prausnitzii as specific butyrate producing faecal bacteria and their 16s rRNA expression was downregulated in HCC patients. In vitro study revealed the presence of sodium butyrate also decreased the cell viability as well as enhanced cell apoptosis of both parental and resistant HepG2 cells. Interestingly, sodium butyrate also decreased the expression of both sorafenib-targeted miR-7641 and miR-199. Further, combination of both sodium butyrate and antimiR-7641 or antimiR-199 also increased apoptosis and decreased viability of resistant cells.

Conclusion

This is first study to unravel the association of butyrate producing bacteria with HCC patients and the significance of bacterial metabolite butyrate as anti-tumour in sorafenib resistant hepatocellular carcinoma. The study also demonstrated the plausible new aspects of bacterial metabolite butyrate association with sorafenib-targeted miRNAs (miR-7641 and miR-199). Hence, the study highlighted the therapeutic potential of bacterial metabolite butyrate that might improve the clinical management of hepatocellular carcinoma.

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All the Raw research data is analyzed and it is incorporated as graphs, figures and tables in the form of present Manuscript.

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Funding

RK and SK awarded JRF/SRF fellowship from ICMR, New Delhi during their PhD work.

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Author notes

  1. Mukesh Kumar and Ramanpreet Kaur have contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education & Research (PGIMER), Chandigarh, 160012, India

    Mukesh Kumar, Ramanpreet Kaur, Shruthi Kanthaje & Anuradha Chakraborti

  2. Department of Hepatology, Postgraduate Institute of Medical Education & Research (PGIMER), Chandigarh, 160012, India

    Ramanpreet Kaur & Radha K. Dhiman

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  1. Mukesh Kumar
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  2. Ramanpreet Kaur
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  5. Anuradha Chakraborti
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Contributions

R.K. and M.K. have participated in the study concept and its design, acquisition of data and its analysis, and also in manuscript preparation. S.K. and R.K.D. have critically revised the manuscript. A.C. has participated in the supervision of study, interpretation of data for important intellectual content.

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Correspondence to Anuradha Chakraborti.

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Kumar, M., Kaur, R., Kanthaje, S. et al. Bacterial metabolite butyrate in modulating sorafenib-targeted microRNAs to curtail its resistance in hepatocellular carcinoma. J Cancer Res Clin Oncol 149, 5823–5839 (2023). https://doi.org/10.1007/s00432-022-04544-7

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