Mutant p53s and chromosome 19 microRNA cluster overexpression regulate cancer testis antigen expression and cellular transformation in hepatocellular carcinoma

AbstractA subset of hepatocellular carcinoma (HCC) overexpresses the chromosome 19 miRNA cluster (C19MC) and is associated with an undifferentiated phenotype marked by overexpression of cancer testis antigens (CTAs) including anti-apoptotic melanoma-A antigens (MAGEAs). However, the regulation of C19MC miRNA and MAGEA expression in HCCs are not understood. Here we show that, C19MC overexpression is tightly linked to a sub-set of HCCs with transcription-incompetent p53. Using next-generation and Sanger sequencing we found that, p53 in Hep3B cells is impaired by TP53-FXR2 fusion, and that overexpression of the C19MC miRNA-520G in Hep3B cells promotes the expression of MAGEA-3, 6 and 12 mRNAs. Furthermore, overexpression of p53-R175H and p53-R273H mutants promote miR-520G and MAGEA RNA expression and cellular transformation. Moreover, IFN-γ co-operates with miR-520G to promote MAGEA expression. On the other hand, metals such as nickel and zinc promote miR-526B but not miR-520G, to result in the suppression of MAGEA mRNA expression, and evoke cell death through mitochondrial membrane depolarization. Therefore our study demonstrates that a MAGEA-promoting network involving miR-520G, p53-defects and IFN-γ that govern cellular transformation and cell survival pathways, but MAGEA expression and survival are counteracted by nickel and zinc combination.

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Indazolo[3,2-b]quinazolinones Attack Hepatocellular Carcinoma Hep3B Cells by Inducing Mitochondrial-Dependent Apoptosis and Inhibition of Nrf2/ARE Signaling Pathway

Current Molecular Medicine ◽

10.2174/1566524016666161128114444 ◽

2016 ◽

Vol 16 (9) ◽

pp. 820-828 ◽

Cited By ~ 5

Author(s):

Y. Zhang ◽

R. Qiao ◽

D. He ◽

Z. Zhao ◽

S. Yang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Hep3b Cells

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Expression of Cancer Testis Antigens in Tumor-Adjacent Normal Liver Is Associated with Post-Resection Recurrence of Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13102499 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2499

Author(s):

Lisanne Noordam ◽

Zhouhong Ge ◽

Hadiye Özturk ◽

Michail Doukas ◽

Shanta Mancham ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Normal Liver ◽

Occult Metastasis ◽

Recurrence Rates ◽

Curative Intent ◽

Cancer Testis Antigens ◽

Negative Prognostic Factor ◽

Increased Risk ◽

Hcc Recurrence ◽

Cancer Testis

High recurrence rates after resection of hepatocellular carcinoma (HCC) with curative intent impair clinical outcomes of HCC. Cancer/testis antigens (CTAs) are suitable targets for cancer immunotherapy if selectively expressed in tumor cells. The aims were to identify CTAs that are frequently and selectively expressed in HCC-tumors, and to investigate whether CTAs could serve as biomarkers for occult metastasis. Tumor and paired tumor-free liver (TFL) tissues of HCC-patients and healthy tissues were assessed for mRNA expression of 49 CTAs by RT-qPCR and protein expression of five CTAs by immunohistochemistry. Twelve CTA-mRNAs were expressed in ≥10% of HCC-tumors and not in healthy tissues except testis. In tumors, mRNA and protein of ≥ 1 CTA was expressed in 78% and 71% of HCC-patients, respectively. In TFL, CTA mRNA and protein was found in 45% and 30% of HCC-patients, respectively. Interestingly, CTA-expression in TFL was an independent negative prognostic factor for post-resection HCC-recurrence and survival. We established a panel of 12 testis-restricted CTAs expressed in tumors of most HCC-patients. The increased risk of HCC-recurrence in patients with CTA expression in TFL, suggests that CTA-expressing (pre-)malignant cells may be a source of HCC-recurrence, reflecting the relevance of targeting these to prevent HCC-recurrence.

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ROS-Mediated Anti-Tumor Effect of Coptidis Rhizoma against Human Hepatocellular Carcinoma Hep3B Cells and Xenografts

International Journal of Molecular Sciences ◽

10.3390/ijms22094797 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4797

Author(s):

So Young Kim ◽

Cheol Park ◽

Min Yeong Kim ◽

Seon Yeong Ji ◽

Hyun Hwangbo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Ethanol Extract ◽

Pharmacological Intervention ◽

Ros Generation ◽

Apoptosis Pathway ◽

Invasion And Migration ◽

Intrinsic Apoptosis Pathway ◽

Anti Cancer ◽

Coptidis Rhizoma ◽

Hep3b Cells

Coptidis Rhizoma is the dried rhizome from the Coptis chinensis Franch. that has been shown to have a number of beneficial pharmacological properties including antioxidant, anti-inflammatory, and anti-cancer effects. However, the anti-cancer effects of Coptidis Rhizoma on hepatocellular carcinoma (HCC) remain unclear. In this study, we investigated the anti-cancer properties of Coptidis Rhizoma ethanol extract (CR) in HCC Hep3B cells and in a xenograft mouse model. Our results showed that the CR significantly inhibited cell growth and induced apoptosis in Hep3B cells through increased expression of Bcl-2 associated x-protein (Bax) and cleavage of poly-ADP ribose polymerase (PARP), reduced expression of Bcl-2, and activated caspases. CR also increased the generation of intracellular reactive oxygen species (ROS), which caused a loss of mitochondrial membrane potential (MMP, ΔΨm) and activation of the mitochondria-mediated intrinsic apoptosis pathway. Moreover, N-acetylcysteine (NAC), a ROS inhibitor, markedly blocked the effects of CR on apoptotic pathways. CR also induced the expression of light chain 3 (LC3)-I/II, a key autophagy regulator, whereas CR-mediated autophagy was significantly suppressed by NAC. In addition, pre-treatment with NAC perfectly attenuated the inhibition of cell invasion and migration of CR-stimulated Hep3B cells. Furthermore, oral administration of CR suppressed Hep3B tumor growth in xenograft mice without toxicity, alterations to body weight, or changes in hematological and biochemical profiles. Taken together, our findings suggest that CR has anti-tumor effects that result from ROS generation, and may be a potential pharmacological intervention for HCC.

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Comparison of the survival implications of tumour-associated versus cancer-testis antigen expression in acute myeloid leukaemia

British Journal of Haematology ◽

10.1111/j.1365-2141.2006.06454.x ◽

2007 ◽

Vol 136 (3) ◽

pp. 510-512 ◽

Cited By ~ 2

Author(s):

Barbara-ann Guinn ◽

Khalid Tobal ◽

Ken I. Mills

Keyword(s):

Acute Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

Antigen Expression ◽

Cancer Testis Antigen ◽

Acute Myeloid ◽

Cancer Testis

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Cancer-testis antigen expression is shared between epithelial ovarian cancer tumors

Gynecologic Oncology ◽

10.1016/j.ygyno.2014.03.253 ◽

2014 ◽

Vol 133 ◽

pp. 95

Author(s):

A.E. Garcia-Soto ◽

J.A. Lucci ◽

E. Podack ◽

T. Schreiber ◽

E.D. Schroeder

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Antigen Expression ◽

Cancer Testis Antigen ◽

Cancer Testis

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Amygdalin promotes the activity of T cells to suppress the progression of HBV-related hepatocellular carcinoma via the JAK2/STAT3 signaling pathway

BMC Infectious Diseases ◽

10.1186/s12879-020-05713-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ruoyu Wang ◽

Dong Zhang ◽

Kewei Sun ◽

Jianping Peng ◽

Wenfang Zhu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Cell Viability ◽

Caspase 3 ◽

Invasion And Migration ◽

Ifn Γ ◽

And Migration ◽

Cellular Immune

Abstract Background Hepatitis B virus (HBV) infection is a high-risk factor of hepatocellular carcinoma (HCC). Cellular immune responses are essential for HCC development, and the CD4+ and CD8+ T subtypes are identified as the primary anti-tumor immune cells. In the study, we investigated the effect and mechanism of amygdalin in the cellular immune response in HBV-related HCC and HCC progression. Methods The cell proliferation was examined by MTT analysis. Cells metastasis ability was detected by Invasion and migration assays. Quantification of apoptotic cells was performed with Flow cytometer assay. The protein levels of p-STAT3, STAT3, p-JAK2, JAK2, caspase-3, cleaved caspase-3 were detected by performing immunoblotting assays. Results We demonstrate that amygdalin treatment could rescue the HBV-T cell viability and IFN-γ and TNF-αproduction. In HBV-T cells, the MFI levels of CD8+ are lower than that in NC-T cells. Moreover, the phosphorylation levels of STAT3 and JAK2 are higher in HBV-T cells, compared to those in NC-T cells, and then reduced by amygdalin treatment. Co-culture with HBV-T cells could reduce IFN-γ and TNF-α, production while increase IL-6 and IL-10 production in HepG2.2.15 cells; these alterations could be partially reversed by amygdalin pretreatment. Finally, co-culture with HBV-T cells significantly promoted the cell viability, inhibited the apoptosis, and promoted the migration of HepG2.2.15 cells, and these alterations could be partially reversed by amygdalin treatment. Conclusion Our findings provide a rationale for further studies on the functions and mechanism of amygdalin inhibiting HBV-related HCC cell proliferation, invasion, and migration via T cell-mediated tumor immunity.

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