Babao Dan decreases hepatocarcinogenesis by inhibiting hepatic progenitor cells malignant transformation via down-regulating toll-like receptor 4

Lei Liang; Lu-Yao Zhang; Wen-Ting Liu; Chen Zong; Lu Gao; Rong Li; Qiu-Dong Zhao; Na-Ping Zhao; Li-Xin Wei; Li Zhang; Zhi-Peng Han

doi:10.3389/fonc.2023.1073859

Babao Dan decreases hepatocarcinogenesis by inhibiting hepatic progenitor cells malignant transformation via down-regulating toll-like receptor 4

Front Oncol. 2023 May 12:13:1073859. doi: 10.3389/fonc.2023.1073859. eCollection 2023.

Authors

Lei Liang^{1

2

3}, Lu-Yao Zhang^{4

5

6}, Wen-Ting Liu¹, Chen Zong¹, Lu Gao¹, Rong Li¹, Qiu-Dong Zhao¹, Na-Ping Zhao⁴, Li-Xin Wei¹, Li Zhang^{4

5}, Zhi-Peng Han¹

Affiliations

¹ Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China.
² Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China.
³ Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, China.
⁴ Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China.
⁵ Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China.
⁶ School of Pharmacy, Anhui Medical University, Hefei, China.

Abstract

Background: Babao Dan (BBD) is a traditional Chinese medicine that has been widely used as a complementary and alternative medicine to treat chronic liver diseases. In this study, we aimed to observe the effect of BBD on the incidence of diethylnitrosamine (DEN)-initiated hepatocellular carcinoma formation in rats and explored its possible mechanism.

Methods: To verify this hypothesis, BBD was administrated to rats at a dose of 0.5g/kg body weight per two days from the 9th to 12th week in HCC-induced by DEN. Liver injury biomarkers and hepatic inflammatory parameters were evaluated by histopathology as well as serum and hepatic content analysis. We applied immunohistochemical analysis to investigate the expression of CK-19 and SOX-9 in liver tissues. The expression of TLR4 was determined by immunohistochemical, RT-PCR, and western blot analysis. Furthermore, we also detected the efficacy of BBD against primary HPCs neoplastic transformation induced by LPS.

Results: We observed that DEN could induce hepatocarcinogenesis, and BBD could obviously decrease the incidence. The biochemical and histopathological examination results confirmed that BBD could protect against liver injury and decrease inflammatory infiltration. Immunohistochemistry staining results showed that BBD could effectively inhibit the ductal reaction and the expression of TLR4. The results showed that BBD-serumcould obviously inhibit primary HPCs neoplastic transformation induced by regulating the TLR4/Ras/ERK signaling pathway.

Conclusion: In summary, our results indicate that BBD has potential applications in the prevention and treatment of HCC, which may be related to its effect on hepatic progenitor cells malignant transformation via inhibiting the TLR4/Ras/ERK signaling pathway.

Keywords: Babao Dan; hepatic progenitor cell; hepatocellular carcinoma; lipopolysaccharides; toll-like receptor 4.

Grants and funding

This project was supported by the National Key R&D Program of China (Grant NO. 2018YFA0107500); National Natural Science Foundation of China (Grant NO. 81630070, 81673641, 81872243, 81972599, 82173276, 82073032, 82073037); Special Funds for National Key Sci-Tech Special Project of China (Grant NO. 2018ZX10723204-005-004).