Kangxianruangan granule‑containing serum mediated inhibition of hepatic oval cell differentiation into hepatocellular carcinoma cells via the Wnt‑1/β‑catenin signaling pathway.

Publisher: D. A. Spandidos Country of Publication: Greece NLM ID: 101475259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1791-3004 (Electronic) Linking ISSN: 17912997 NLM ISO Abbreviation: Mol Med Rep Subsets: MEDLINE

Original Publication: Athens, Greece : D. A. Spandidos

Carcinoma, Hepatocellular/*prevention & control ; Cell Transformation, Neoplastic/*drug effects ; Drugs, Chinese Herbal/*administration & dosage ; Liver Neoplasms, Experimental/*prevention & control ; Wnt Signaling Pathway/*drug effects; Animals ; Carcinoma, Hepatocellular/chemically induced ; Carcinoma, Hepatocellular/pathology ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Transformation, Neoplastic/chemically induced ; Cell Transformation, Neoplastic/pathology ; Disease Models, Animal ; Humans ; Liver/cytology ; Liver/pathology ; Liver Neoplasms, Experimental/chemically induced ; Liver Neoplasms, Experimental/pathology ; Male ; Methylnitronitrosoguanidine/toxicity ; Rats ; Tumor Microenvironment/drug effects

Hepatocellular carcinoma is a malignancy with poor clinical prognosis. Hepatic oval cells (HOCs) tend to differentiate into cancerous hepatocellular carcinoma cells (HCCs) in the tumor microenvironment. The purpose of the present study was to explore the role of kangxianruangan granule (KXRG)‑containing serum in inhibiting the differentiation of HOCs into HCCs via the Wnt‑1/β‑catenin signaling pathway. N‑methyl‑N'‑nitro‑N‑nitrosoguanidine (MNNG) was applied to induce the transformation of the rat HOC cell line WB‑F344 into HCCs. The overexpression plasmid, Wnt‑1‑up, was utilized to increase Wnt‑1 expression. Subsequently, high, medium and low concentrations of KXRG were applied to MNNG‑treated WB‑F344 cells to assess the inhibitory effect of KXRG on cell differentiation. Flow cytometry was conducted to detect the cell cycle distribution, apoptotic rate and expression of cytokeratin‑19 (CK‑19) protein in cells. An immunofluorescence double staining protocol was used to detect the expression of Wnt‑1 and β‑catenin. ELISAs were performed to detect α fetoprotein in the cell supernatants. Reverse transcription‑quantitative PCR and western blotting were conducted to detect the mRNA and protein expression levels of Wnt‑1, β‑catenin, Cyclin D1, C‑myc, matrix metalloproteinase‑7 (MMP‑7), Axin2 and epithelial cell adhesion molecule (EpCAM) in cells. Compared with the normal group, the apoptotic rate, proportion of S phase cells, concentration of AFP in the cell supernatant, level of CK‑19 protein, and mRNA and protein expression levels of Wnt‑1, β‑catenin, Cyclin D1, C‑myc, MMP‑7, Axin2 and EpCAM were all significantly increased in the model group. Addition of KXRG significantly reduced the aforementioned indicators compared with the model group. Moreover, Wnt‑1 overexpression further increased the aforementioned indicators compared with the model group, whereas KXRG significantly inhibited these effects. The results indicated that KXRG inhibited the differentiation of HOCs into HCCs via the Wnt‑1/β‑catenin signaling pathway, which suggested the potential clinical application of KXRG for the prevention of hepatocellular carcinoma.

World J Gastroenterol. 2017 May 7;23(17):3066-3076. (PMID: 28533663)
Medicine (Baltimore). 2018 Dec;97(49):e13532. (PMID: 30544457)
World J Gastroenterol. 2016 Mar 28;22(12):3305-14. (PMID: 27022212)
Cancer Lett. 2020 Apr 28;476:140-151. (PMID: 32061951)
Semin Liver Dis. 2019 Feb;39(1):26-42. (PMID: 30809789)
Nat Rev Gastroenterol Hepatol. 2019 Oct;16(10):589-604. (PMID: 31439937)
Cancers (Basel). 2019 Nov 01;11(11):. (PMID: 31683891)
J Immunother Cancer. 2019 Nov 29;7(1):333. (PMID: 31783782)
Clin Transl Oncol. 2015 Mar;17(3):230-7. (PMID: 25257837)
Methods. 2001 Dec;25(4):402-8. (PMID: 11846609)
Nat Rev Gastroenterol Hepatol. 2019 Feb;16(2):121-136. (PMID: 30451972)
Mol Cancer. 2018 Mar 14;17(1):73. (PMID: 29540185)
Zhonghua Gan Zang Bing Za Zhi. 2019 Jul 20;27(7):483-486. (PMID: 31357771)
Front Oncol. 2019 Nov 18;9:1248. (PMID: 31803621)
Gastroenterology. 2015 Jun;148(7):1294-310. (PMID: 25747274)
PLoS One. 2015 Dec 11;10(12):e0144433. (PMID: 26658815)
EMBO J. 2019 Jan 15;38(2):. (PMID: 30425074)
Eur J Nutr. 2019 Dec;58(8):3207-3219. (PMID: 30460610)
Front Biosci (Elite Ed). 2012 Jan 01;4:1157-69. (PMID: 22201943)
Mol Med Rep. 2017 Dec;16(6):8420-8426. (PMID: 28983609)
Hepatology. 2019 Oct;70(4):1231-1245. (PMID: 30963603)
World J Gastroenterol. 2016 Jan 14;22(2):823-32. (PMID: 26811628)
Clin Transl Oncol. 2015 Nov;17(11):935. (PMID: 26282921)
PLoS One. 2013 Nov 15;8(11):e79409. (PMID: 24260215)
Cancer Med. 2019 Nov;8(15):6684-6699. (PMID: 31523930)
World J Gastroenterol. 2019 Apr 28;25(16):1936-1949. (PMID: 31086462)
Cell Death Dis. 2020 May 4;11(5):313. (PMID: 32366840)
Int J Cancer. 2021 Apr 5;:. (PMID: 33818764)
Am J Transl Res. 2020 May 15;12(5):2099-2109. (PMID: 32509204)
Clin Res Hepatol Gastroenterol. 2019 Aug;43(4):373-386. (PMID: 30377095)
Int J Mol Med. 2019 Dec;44(6):2276-2288. (PMID: 31661124)
Liver Int. 2017 Sep;37(9):1260-1271. (PMID: 28135758)
Mol Cancer. 2009 Sep 24;8:76. (PMID: 19778454)
Cancer Lett. 2011 Mar 28;302(2):91-9. (PMID: 21247686)

Keywords: Wnt‑1/β‑catenin signaling pathway; hepatic oval cells; hepatocellular carcinoma cells; kangxianruangan granule‑containing serum

0 (Drugs, Chinese Herbal)
0 (kangxian ruangan)
12H3O2UGSF (Methylnitronitrosoguanidine)

Date Created: 20211216 Date Completed: 20220309 Latest Revision: 20220309

20240829

PMC8711029

10.3892/mmr.2021.12571

34913065