Hepatocellular and Cholangiolar Carcinoma-Derived Cell Lines Reveal Distinct Sets of Chromosomal Imbalances

Zhou

et al. 2023

Preprint

Background Polycomb protein suppressor of zeste 12 (SUZ12) has been widely revealed involving in development and diverse physiopathology processes. However, the roles of SUZ12 in hepatocellular carcinoma (HCC) remain largely unknown. Methods Tissue microarray was used to examine the expression level of SUZ12. The gain- and loss- of function analysis were conducted to evaluate the effects of SUZ12 on the proliferation, migration and invasion of HCC cells. Meanwhile, luciferase reporter assay and RT-PCR assay were conducted to examine the effect of SUZ12 on transcriptional activity of chemokine receptors 7 (CXCR7). Results The expression level of SUZ12 was positively associated with HCC development, as revealed by tissue microarray analysis. Further gain- and loss- of function analysis demonstrated that SUZ12 promoted the proliferation, migration and invasion of HCC. Mechanistically, we found that SUZ12 could upregulate the expression of CXCR7 at the transcriptional level in HCC cells, and CXCR7 was revealed to contribute to the tumor-promoting roles of SUZ12. Of interest, luciferase reporter assay revealed SUZ12 positively controlled the CXCR7 via direct promoter combination but not epigenetic suppression. Moreover, high SUZ12 expression was positively correlated with CXCR7 in advanced patients with portal vein tumor thrombus. Conclusion Our findings indicate that SUZ12 plays pro-oncogenic roles in the progression of HCC, partially by activating CXCR7 signaling, especially in HCC patients with portal vein tumor thrombus. The SUZ12/CXCR7 axis may serve as a potential therapeutic target for treatments of advanced HCC patients.

Section: Suz12 Performs High Expression In Hccsupporting

confidence: 52%

SUZ12/CXCR7 axis promotes invasion potential and is associated with portal vein tumor thrombus in hepatocellular carcinoma

Zhou

et al. 2023

Preprint

“…One of the reasons for this could be the highly expressed phase II enzyme, Uridine 5'-diphospho-glucuronosyltransferase level in HepG2 cells, which possibly catalyze the conjugation of these compounds into hydrophilic glucuronide derivatives that might possess stronger cytotoxicity (Strassburg et al, 1998;Westerink and Schoonen, 2007). Another reason of the relatively cytotoxic resistance of HeLa and Caco-2 cells could be their aneuploid nature and chromosome instability, compared to a relatively near-diploid karyotype of HepG2 cells (Wilkens et al, 2012). Aneuploid and chromosome instability were believed to contribute to the acquisition of drug resistance by enhancing adaptation capacity to withstand cellular stresses (Lee et al, 2011;McClelland et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Distinct Responses of Cytotoxic Ganoderma lucidum Triterpenoids in Human Carcinoma Cells

Ruan

Wei

Popovich

2015

Phytotherapy Research

The medicinal mushroom Ganoderma lucidum is well recognized for its effective cancer-preventative and therapeutic properties, while specific components responsible for these anticancer effects are not well studied. Six triterpenoids that are ganolucidic acid E, lucidumol A, ganodermanontriol, 7-oxo-ganoderic acid Z, 15-hydroxy-ganoderic acid S, and ganoderic acid DM were isolated and identified from an extract of the mushroom. All compounds reduced cell growth in three human carcinoma cells (Caco-2, HepG2, and HeLa cells) dose dependently with LC50s from 20.87 to 84.36 μM. Moreover, the six compounds induced apoptosis in HeLa cells with a maximum increase (22%) of sub-G1 accumulations and 43.03% apoptotic cells in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay (15-hydroxy-ganoderic acid S treatment). Apoptosis was further confirmed by annexin-V staining. Four of the compounds also caused apoptosis in Caco-2 cells with maximum 9.5% increase of sub-G1 accumulations (7-oxo-ganoderic acid Z treatment) and maximum 29.84% apoptotic cells in TUNEL assay (ganoderic acid DM treatment). Contrarily, none of the compounds induced apoptosis in HepG2 cells. The different responses of the three cell lines following these treatments indicated that the bioactive properties of these compounds may vary from cells of different sites of origin and are likely acting under diverse regulatory mechanisms.

Molecular Therapy - Nucleic Acids

“…Hep3B cells (hepatoma cells with a ploidy status of n = 3.2, see Wilkens et al 95 ; for mutations in cancer genes see Table S1 in Ewald) 96 were plated in 6-well plates in complete medium and transfected with a linearized plasmid containing the STAT3-inducible promoter rPAP1 35,36 in front of the secreted Cypridina luciferase gene, using the PromoFectin-Hepatocyte reagent (PromoCell, Bio-Connect, Huissen, the Netherlands), following the manufacturer's protocol. 4 h later, serum-reduced Optim-MEM medium (Life Technologies, Merelbeke, Belgium) was replaced by normal DMEM.…”

Section: Materials and Cell Culturementioning

confidence: 99%

Modulation of the IL-6-Signaling Pathway in Liver Cells by miRNAs Targeting gp130, JAK1, and/or STAT3

Servais

Kirchmeyer

Hamdorf

et al. 2019

Interleukin-6 (IL-6)-type cytokines share the common receptor glycoprotein 130 (gp130), which activates a signaling cascade involving Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) transcription factors. IL-6 and/or its signaling pathway is often deregulated in diseases, such as chronic liver diseases and cancer. Thus, the identification of compounds inhibiting this pathway is of interest for future targeted therapies. We established novel cellular screening systems based on a STAT-responsive reporter gene ( Cypridina luciferase ). Of a library containing 538 microRNA (miRNA) mimics, several miRNAs affected hyper-IL-6-induced luciferase activities. When focusing on candidate miRNAs specifically targeting 3′ UTRs of signaling molecules of this pathway, we identified, e.g., miR-3677-5p as a novel miRNA affecting protein expression of both STAT3 and JAK1, whereas miR-16-1-3p, miR-4473, and miR-520f-3p reduced gp130 surface expression. Interestingly, combination treatment with 2 or 3 miRNAs targeting gp130 or different signaling molecules of the pathway did not increase the inhibitory effects on phospho-STAT3 levels and STAT3 target gene expression compared to treatment with single mimics. Taken together, we identified a set of miRNAs of potential therapeutic value for cancer and inflammatory diseases, which directly target the expression of molecules within the IL-6-signaling pathway and can dampen inflammatory signal transduction.