Cell Cycle Progression or Translation Control Is Not Essential for Vesicular Stomatitis Virus Oncolysis of Hepatocellular Carcinoma

Marozin, Sabrina; Toni, Enrico N. De; Rizzani, Antonia; Altomonte, Jennifer; Jünger, Alexandra; Schneider, Günter; Thasler, Wolfgang E.; Kato, Naoya; Schmid, Roland M.; Ebert, Oliver

doi:10.1371/journal.pone.0010988

Cited by 10 publications

(11 citation statements)

References 48 publications

(74 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In many cancer cell types, specific genes associated with type I IFN signaling are transcriptionally downregulated or functionally inactive (Balachandran and Barber, 2004; Marozin et al, 2008; Marozin et al, 2010; Moussavi et al, 2010; Zhang et al, 2010). Also, type I IFN mediated responses can be inhibited by MEK/ERK signaling, which is often upregulated in cancer cells (Noser et al, 2007), or by epigenetic silencing of IFN responsive transcription factors IRF7 or IRF5 (Li and Tainsky, 2011).…”

Section: Discussionmentioning

confidence: 99%

An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells

et al. 2015

View full text Add to dashboard Cite

Virus-encoded tumor suppressor p53 transgene expression has been successfully used in vesicular stomatitis virus (VSV) and other oncolytic viruses (OVs) to enhance their anticancer activities. However, p53 is also known to inhibit virus replication via enhanced type I interferon (IFN) antiviral responses. To examine whether p53 transgenes enhance antiviral signaling in human pancreatic ductal adenocarcinoma (PDAC) cells, we engineered novel VSV recombinants encoding human p53 or the previously described chimeric p53-CC, which contains the coiled-coil (CC) domain from breakpoint cluster region (BCR) protein and evades the dominant-negative activities of endogenously expressed mutant p53. Contrary to an expected enhancement of antiviral signaling by p53, our global analysis of gene expression in PDAC cells showed that both p53 and p53-CC dramatically inhibited type I IFN responses. Our data suggest that this occurs through p53-mediated inhibition of the NF-κB pathway. Importantly, VSV-encoded p53 or p53-CC did not inhibit antiviral signaling in non-malignant human pancreatic ductal cells, which retain their resistance to all VSV recombinants. To the best of our knowledge, this is the first report of p53-mediated inhibition of antiviral signaling, and it suggests that OV-encoded p53 can simultaneously produce anticancer activities while assisting, rather than inhibiting, virus replication in cancer cells.

show abstract

Section: Discussionmentioning

confidence: 99%

An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells

et al. 2015

View full text Add to dashboard Cite

show abstract

“…The oncoselectivity of VSV is mainly based on defective or reduced type I IFN responses in cancer cells (Barber, 2004; Lichty et al, 2004; Stojdl et al, 2000b, 2003) as these responses are generally anti-proliferative, anti-angiogenic, and pro-apoptotic (Wang et al, 2011), and therefore unfavorable for tumor formation. Downregulation or inactivation of specific genes associated with type I IFN responses (such as PKR, IRF3, or IFN receptor) were shown in some cancer types (Balachandran and Barber, 2004; Marozin et al, 2008, 2010; Moussavi et al, 2010; Zhang et al, 2010). IFN signaling can also be inhibited by MEK/ERK signaling (Noser et al, 2007) or by epigenetic silencing of IFN responsive transcription factors IRF7 or IRF5 (Li and Tainsky, 2011).…”

Section: Replicationmentioning

confidence: 99%

Understanding and altering cell tropism of vesicular stomatitis virus

Hastie¹,

Cataldi²,

Marriott³

et al. 2013

Virus Research

105

106

View full text Add to dashboard Cite

Vesicular stomatitis virus (VSV) is a prototypic nonsegmented negative-strand RNA virus. VSV’s broad cell tropism makes it a popular model virus for many basic research applications. In addition, a lack of preexisting human immunity against VSV, inherent oncotropism and other features make VSV a widely used platform for vaccine and oncolytic vectors. However, VSV’s neurotropism that can result in viral encephalitis in experimental animals needs to be addressed for the use of the virus as a safe vector. Therefore, it is very important to understand the determinants of VSV tropism and develop strategies to alter it. VSV glycoprotein (G) and matrix (M) protein play major roles in its cell tropism. VSV G protein is responsible for VSV broad cell tropism and is often used for pseudotyping other viruses. VSV M affects cell tropism via evasion of antiviral responses, and M mutants can be used to limit cell tropism to cell types defective in interferon signaling. In addition, other VSV proteins and host proteins may function as determinants of VSV cell tropism. Various approaches have been successfully used to alter VSV tropism to benefit basic research and clinically relevant applications.

show abstract

“…9). Indeed, altered expression of these cell-cycle regulatory proteins is associated with HCC growth (31)(32)(33). Although S-phase progression can also be modulated by CDK2/cyclin E, effects on cell growth after inhibition of TUC338 were noted in Huh7 cells, which do not express p21 and cyclin E (34-36), making it unlikely that the effects of TUC338 on cell-cycle progression involved these proteins.…”

mentioning

confidence: 99%

Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma

Braconi¹,

Valeri²,

Kogure³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

201

163

View full text Add to dashboard Cite

Although expression of non-protein-coding RNA (ncRNA) can be altered in human cancers, their functional relevance is unknown. Ultraconserved regions are noncoding genomic segments that are 100% conserved across humans, mice, and rats. Conservation of gene sequences across species may indicate an essential functional role, and therefore we evaluated the expression of ultraconserved RNAs (ucRNA) in hepatocellular cancer (HCC). The global expression of ucRNAs was analyzed with a custom microarray. Expression was verified in cell lines by real-time PCR or in tissues by in situ hybridization using tissue microarrays. Cellular ucRNA expression was modulated with siRNAs, and the effects on global gene expression and growth of human and murine HCC cells were evaluated. Fifty-six ucRNAs were aberrantly expressed in HepG2 cells compared with nonmalignant hepatocytes. Among these ucRNAs, the greatest change was noted for ultraconserved element 338 (uc.338), which was dramatically increased in human HCC compared with noncancerous adjacent tissues. Although uc.338 is partially located within the poly(rC) binding protein 2 (PCBP2) gene, the transcribed ncRNA encoding uc.338 is expressed independently of PCBP2 and was cloned as a 590-bp RNA gene, termed TUC338. Functional gene annotation analysis indicated predominant effects on genes involved in cell growth. These effects were experimentally demonstrated in both human and murine cells. siRNA to TUC338 decreased both anchorage-dependent and anchorage-independent growth of HCC cells. These studies identify a critical role for TUC338 in regulation of transformed cell growth and of transcribed ultraconserved ncRNA as a unique class of genes involved in the pathobiology of HCC.liver cancer | hepatocarcinoma | exaptation | transposon

show abstract

Cell Cycle Progression or Translation Control Is Not Essential for Vesicular Stomatitis Virus Oncolysis of Hepatocellular Carcinoma

Cited by 10 publications

References 48 publications

An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells

An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells

Understanding and altering cell tropism of vesicular stomatitis virus

Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma

Contact Info

Product

Resources

About