title: Reversal of liver cancer-associated stellate cell-induced stem-like characteristics in SMMC-7721 cells by 8-bromo-7-methoxychrysin via inhibiting STAT3 activation.
abstract: Hepatic stellate cells (HSCs) that are activated by human hepatocellular carcinoma (HCC) cells secrete a variety of cytokines, which are the main component of the HCC microenvironment. We aimed to determine whether 8-bromo-7-methoxychrysin (BrMC) could interfere in cross-talk of the human hepatic stellate cell line LX-2 and liver cancer stem-like cells (LCSLCs) to inhibit the characteristics of LCSLCs endowed with the capacity of sustaining human hepatocellular carcinoma (HCC) self-renewal and progression, and to identify its potential mechanism of action. We found that the levels of fibroblast activation protein (FAP) were augmented in LX-2 cells treated with the conditioned medium of LCSLCs (LCSLC-CM) compared to those cultured with routine medium, indicating that the LCSLC-CM can activate LX-2 cells to become liver cancer-associated stellate cells (LCAHSCs). Furthermore, sphere forming capability of SMMC-7721 cells was enhanced and stem cell-related protein expression was significantly increased following treatment with the conditioned medium of LCAHSCs (LCAHSC-CM). Moreover, the level of p-STAT3 was increased in LX-2 cells treated with LCSLC-CM and BrMC reduced expression of p-STAT3. Combination of BrMC and the selective inhibitor of STAT3 cucurbitacin I (JSI-124) synergistically suppressed the LCSLC characteristics in SMMC-7721 cells. Collectively, our data showed that BrMC inhibited the interaction between LX-2 cells and HCC-derived CSCs, and did so potentially through modulation of the STAT3 pathway. Future therapeutic strategies employing anti-CSC therapy should confirm the potential of cucurbitacin I (JSI-124) and BrMC as potent therapeutic agents.
authors.affiliation: Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Kaiqun
authors.initials: K
authors.lastname: Ren
authors.affiliation: Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Meifang
authors.initials: M
authors.lastname: Quan
authors.affiliation: Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Song
authors.affiliation: Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zou
authors.affiliation: Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Duo
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Cao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005419:Flavonoids / Q000494:pharmacology*; D055166:Hepatic Stellate Cells / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014315:Triterpenes / Q000493:pharmacokinetics
chemical_list: C552860:8-bromo-7-methoxychrysin; D000970:Antineoplastic Agents; D005419:Flavonoids; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014315:Triterpenes; C038106:cucurbitacin I