Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin

Natural killer (NK) cell-mediated tumor cell eradication could inhibit tumor initiation and progression. However, the factors that regulate NK cell-mediated cancer cell eradication remain unclear. We determined that hepatocellular carcinoma (HCC) cells exhibit transcriptional down-regulation of NK group 2D (NKG2D) ligands and are largely resistant to NK cell-mediated eradication. Because the down-regulation of NKG2D ligands occurred at the transcriptional level, we tested 32 chemical inhibitors of epigenetic regulators for their ability to re-express NKG2D ligands and enhance HCC cell eradication by NK cells and found that Enhancer of zeste homolog 2 (EZH2) was a transcriptional repressor of NKG2D ligands. The inhibition of EZH2 by small-molecule inhibitors or genetic means enhanced HCC cell eradication by NK cells in a NKG2D ligand-dependent manner. Collectively, these results demonstrate that EZH2 inhibition enhances HCC eradication by NK cells and that EZH2 functions, in part, as an oncogene by inhibiting immune response.

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Type III TGF-β Receptor Down-Regulation Promoted Tumor Progression via Complement Component C5a Induction in Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13071503 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1503

Author(s):

Oscar Wai Ho Yeung ◽

Xiang Qi ◽

Li Pang ◽

Hui Liu ◽

Kevin Tak Pan Ng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Progression ◽

Tumor Stage ◽

Complement Component ◽

Soluble Form ◽

Advanced Tumor Stage ◽

Down Regulation ◽

Type Iii ◽

Advanced Tumor ◽

Β Receptor

Background and Aims—Transforming growth factor-beta (TGF-β) signaling orchestrates tumorigenesis and one of the family members, TGF-β receptor type III (TGFβR3), are distinctively under-expressed in numerous malignancies. Currently, the clinical impact of TGFβR3 down-regulation and the underlying mechanism remains unclear in hepatocellular carcinoma (HCC). Here, we aimed to identify the tumor-promoting roles of decreased TGFβR3 expression in HCC progression. Materials and Methods—For clinical analysis, plasma and liver specimens were collected from 100 HCC patients who underwent curative resection for the quantification of TGFβR3 by q-PCR and ELISA. To study the tumor-promoting mechanism of TGFβR3 downregulation, HCC mouse models and TGFβR3 knockout cell lines were applied. Results—Significant downregulation of TGFβR3 and its soluble form (sTGFβR3) were found in HCC tissues and plasma compared to healthy individuals (p < 0.01). Patients with <9.4 ng/mL sTGFβR3 exhibited advanced tumor stage, higher recurrence rate and shorter disease-free survival (p < 0.05). The tumor-suppressive function of sTGFβR3 was further revealed in an orthotopic mouse HCC model, resulting in 2-fold tumor volume reduction. In TGFβR3 knockout hepatocyte and HCC cells, increased complement component C5a was observed and strongly correlated with shorter survival and advanced tumor stage (p < 0.01). Interestingly, C5a activated the tumor-promoting Th-17 response in tumor associated macrophages. Conclusion—TGFβR3 suppressed tumor progression, and decreased expression resulted in poor prognosis in HCC patients through upregulation of tumor-promoting complement C5a.

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Effects of TMEM9 gene on cell progression in hepatocellular carcinoma by RNA interference

Oncology Reports ◽

10.3892/or.2016.4821 ◽

2016 ◽

Vol 36 (1) ◽

pp. 299-305 ◽

Cited By ~ 7

Author(s):

YI ZHANG ◽

YAN RAN ◽

YAN XIONG ◽

ZI-BIAO ZHONG ◽

ZHENG-HUA WANG ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Rna Interference ◽

Cell Progression

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Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia

Blood ◽

10.1182/blood-2011-08-371963 ◽

2011 ◽

Vol 118 (23) ◽

pp. 6087-6096 ◽

Cited By ~ 82

Author(s):

Pekka Jaako ◽

Johan Flygare ◽

Karin Olsson ◽

Ronan Quere ◽

Mats Ehinger ◽

...

Keyword(s):

Bone Marrow ◽

Rna Interference ◽

Ribosomal Protein ◽

Mouse Models ◽

Bone Marrow Failure ◽

Macrocytic Anemia ◽

Down Regulation ◽

Hematopoietic Stem ◽

Diamond Blackfan Anemia ◽

Ribosomal Protein S19

Abstract Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Among these genes, ribosomal protein S19 (RPS19) is mutated most frequently. Generation of animal models for diseases like DBA is challenging because the phenotype is highly dependent on the level of RPS19 down-regulation. We report the generation of mouse models for RPS19-deficient DBA using transgenic RNA interference that allows an inducible and graded down-regulation of Rps19. Rps19-deficient mice develop a macrocytic anemia together with leukocytopenia and variable platelet count that with time leads to the exhaustion of hematopoietic stem cells and bone marrow failure. Both RPS19 gene transfer and the loss of p53 rescue the DBA phenotype implying the potential of the models for testing novel therapies. This study demonstrates the feasibility of transgenic RNA interference to generate mouse models for human diseases caused by haploinsufficient expression of a gene.

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