Biomedical subjects

Yuqiao Shen

Publications and source records attributed to Yuqiao Shen.

8 recordsLinked to original sources

PubMed2026

SLC25A45 as a prognostic biomarker promotes malignant progression via mutant p53 in hepatocellular carcinoma.

BACKGROUND: SLC25A45 belongs to the mitochondrial trimethyllysine carrier protein family. To date, its role in tumor development has not been fully elucidated. Previous studies have demonstrated its pro-tumor function in ovarian cancer; however, research on the expression characteristics, biological roles and underlying regulatory pathways of SLC25A45 in hepatocellular carcinoma (HCC) is limited. This study aims to explore the expression, functional roles, and regulatory pathways of SLC25A45 in HCC. METHODS: This study examined SLC25A45 expression and clinical relevance in HCC using publicly available transcriptomic data. SLC25A45 knockdown cell lines were constructed using PLC/PRF/5, Huh7, and Huh1 cells. Functional assays, including cell proliferation and colony formation assays, were then conducted. To investigate the effects of SLC25A45 knockdown on the malignant phenotypes of HCC cells in vitro, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) analyses were performed to identify potential underlying mechanisms, which were subsequently validated by experimental assays. RESULTS: SLC25A45 was elevated in clinical HCC specimens, and high SLC25A45 expression was correlated with disease progression and poor overall survival (OS). In vitro functional assays demonstrated that SLC25A45 silencing reduced HCC cell proliferation and colony formation. Mechanistically, GSEA indicated that high SLC25A45 expression was significantly enriched in the p53 signaling pathways. SLC25A45 knockdown in HCC cells led to a significant increase in wild-type p53 protein expression, but a substantial decrease in mutant p53 expression. CONCLUSIONS: SLC25A45 is a potential prognostic indicator and may drive HCC tumorigenesis and progression through the differential modulation of the p53 signaling pathways.

SLC25A45↗

PubMed2006

Antitumor activity of an oncolytic adenovirus-delivered oncogene small interfering RNA.

Despite successes in animal models, cancer gene therapy with small interfering RNAs (siRNA) is hindered by the lack of an optimal delivery platform. We examined the applicability of the replication-competent, oncolytic adenovirus, ONYX-411, to deliver a mutant K-ras siRNA transgene to human cancer cells. Proof-of-principle studies showed an additive tumor growth-inhibitory response through siRNA-mediated K-ras knockdown and ONYX-411-mediated cancer cell lysis. A novel construct, termed Internavec (for interfering RNA vector), was generated by cloning a K-ras(v12)-specific siRNA(ras-4) hairpin construct under the control of the human H1 promoter into the deleted E3b region of ONYX-411. Internavec acquired an increase in potency of approximately 10-fold in human cancer cells expressing the relevant K-ras(v12) mutation (H79, H441, and SW480), as defined by a reduction in the effective dose needed to achieve 50% growth inhibition (ED(50)). Internavec remained attenuated in nonmalignant epithelial cells. Daily intratumoral injections of Internavec (five daily injections of 1 x 10(8) plaque-forming units) significantly reduced the growth of s.c. H79 pancreatic cancer xenografts in nu/nu mice by 85.5%, including complete growth suppression in three of five mice. Parental ONYX-411 or ONYX-411-siRNA(GFP) was markedly less effective (47.8% growth reduction, P = 0.03; and 44.1% growth reduction, P = 0.03, respectively). siRNA(ras) transgene activity contributed to cell cycle blockage, increased apoptosis, and marked down-regulation of Ras signaling-related gene expression (AKT2, GSK3 beta, E2F2, and MAP4K5). These findings indicate that Internavec can generate a two-pronged attack on tumor cells through oncogene knockdown and viral oncolysis, resulting in a significantly enhanced antitumor outcome.

Adenocarcinoma↗

PubMed2005

Fighting cancer with vaccinia virus: teaching new tricks to an old dog.

Vaccinia virus has played a huge part in human beings' victory over smallpox. With smallpox being eradicated and large-scale vaccination stopped worldwide, vaccinia has assumed a new role in our fight against another serious threat to human health: cancer. Recent advances in molecular biology, virology, immunology, and cancer genetics have led to the design of novel cancer therapeutics based on vaccinia virus backbones. With the ability to infect efficiently a wide range of host cells, a genome that can accommodate large DNA inserts and express multiple genes, high immunogenicity, and cytoplasmic replication without the possibility of chromosomal integration, vaccinia virus has become the platform of many exploratory approaches to treat cancer. Vaccinia virus has been used as (1) a delivery vehicle for anti-cancer transgenes, (2) a vaccine carrier for tumor-associated antigens and immunoregulatory molecules in cancer immunotherapy, and (3) an oncolytic agent that selectively replicates in and lyses cancer cells.

Animals↗

PubMed2005

Tumor-specific intravenous gene delivery using oncolytic adenoviruses.

In this report, we describe a vector system that specifically delivers transgene products to tumors following intravenous (i.v.) administration. The Escherichia coli cytosine deaminase (CD) gene was placed in the E3B region of the tumor-selective, replication-competent adenovirus ONYX-411, under the control of endogenous viral late gene regulatory elements. Thus, CD expression was directly coupled to the tumor-selective replication of the viral vector. In vitro, CD was expressed efficiently in various human cancer cell lines tested but not in cultured normal human cells, including human hepatocytes. Following i.v. administration into nude mice carrying human tumor xenografts, robust CD activity was detected only in tumors but not in liver or other normal tissues. Levels of CD activity in the tumors increased progressively following i.v. virus administration, correlating closely with virus replication in vivo. Subsequent administration of 5-fluorocytosine (5-FC) demonstrated a trend to improve the antitumor efficacy of these viruses in a mouse xenograft model, presumably due to the intratumoral conversion of 5-FC to the chemotherapeutic drug 5-fluorouracil. We show that the combination of a highly selective oncolytic virus, ONYX-411, with the strategic use of the viral E3B region for transgene insertion provides a powerful platform that allows for tumor-specific, persistent and robust transgene expression after i.v. administration. This technology provides an opportunity to enhance greatly both safety and efficacy of cancer gene therapy.

Adenoviridae↗

PubMed2005

Individualised cancer therapeutics: dream or reality? Therapeutics construction.

The analysis of DNA microarray and proteomic data, and the subsequent integration into functional expression sets, provides a circuit map of the hierarchical cellular networks responsible for sustaining the viability and environmental competitiveness of cancer cells, that is, their robust systematics. These technologies can be used to 'snapshot' the unique patterns of molecular derangements and modified interactions in cancer, and allow for strategic selection of therapeutics that best match the individual profile of the tumour. This review highlights technology that can be used to selectively disrupt critical molecular targets and describes possible vehicles to deliver the synthesised molecular therapeutics to the relevant cellular compartments of the malignant cells. RNA interference (RNAi) involves a group of evolutionarily conserved gene silencing mechanisms in which small sequences of double-stranded RNA or intrinsic antisense RNA trigger mRNA cleavage or translational repression, respectively. Although RNAi molecules can be synthesised to 'silence' virtually any gene, even if upregulated, a mechanism for selective delivery of RNAi effectors to sites of malignant disease remains challenging. The authors will discuss gene-modified conditionally replicating viruses as candidate vehicles for the delivery of RNAi.

Animals↗

PubMed2005

Individualised cancer therapeutics: dream or reality?

Traditional measures for treating metastatic cancer involve identification of the originating organ from which the neoplasm arose and empirical treatment with cytotoxic chemotherapy. Arguably, with the exception of haematological malignancies, demonstration of efficacy in solid tumours has been limited. Over the past half-decade, theoretical and technological advances have resulted in greater application of molecular science to drug design, which has enabled development of new 'targeted' therapeutics. However, generic chemotherapy paradigms have not changed. Establishment of the optimal population for 'targeted' therapeutics based on molecular diagnostics (i.e. genomic and proteomic characterisation) to identify sensitive tumour-host ecosystems in individual patients at the 'bedside', is not being done as part of routine oncology management. This review focuses on the concept of designing individualised therapeutics based on genomic and proteomic profile of malignant tissue. Genetic and epigenetic perturbations in signal pathways drive cancer growth, survival, invasion and metastatic spread. The burgeoning evidence which supports the concept that each patient's cancer has a unique complement of pathogenic genetic and molecular derangements is reviewed. Such evidence supports the strategy of individualised selection of a therapeutic complex from a menu of targeting options that best complements the specific oncomolecular profile of the 'tumour-host' system.

Antineoplastic Agents↗

PubMed2004

Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity.

ONYX-015 is an adenovirus that lacks the E1B-55K gene product for p53 degradation. Thus, ONYX-015 was conceived as an oncolytic virus that would selectively replicate in p53-defective tumor cells. Here we show that loss of E1B-55K leads to the induction, but not the activation, of p53 in ONYX-015-infected primary cells. We use a novel adenovirus mutant, ONYX-053, to demonstrate that loss of E1B-55K-mediated late viral RNA export, rather than p53 degradation, restricts ONYX-015 replication in primary cells. In contrast, we show that tumor cells that support ONYX-015 replication provide the RNA export function of E1B-55K. These data reveal that tumor cells have altered mechanisms for RNA export and resolve the controversial role of p53 in governing ONYX-015 oncolytic selectivity.

Adenoviridae↗

PubMed2003

Developing novel oncolytic adenoviruses through bioselection.

Mutants of human adenovirus 5 (Ad5) with enhanced oncolytic activity were isolated by using a procedure termed bioselection. Two mutants, ONYX-201 and ONYX-203, were plaque purified from a pool of randomly mutagenized Ad5 that was repeatedly passaged in the human colorectal cancer cell line HT29, and they were subsequently characterized. ONYX-201 and ONYX-203 replicated more rapidly in HT29 cells than wild-type Ad5, and they lysed HT29 cells up to 1,000-fold more efficiently. The difference was most profound when cells were infected at a relatively low multiplicity of infection, presumably due to the compounding effects of multiple rounds of infection. This enhanced cytolytic activity was observed not only in HT29 cells but also in many other human cancer cell lines tested. In contrast, the cytotoxicity of the bioselected mutants in a number of normal primary human cells was similar to that of wild-type Ad5, thus enhancing the therapeutic index (cytotoxicity in tumor cells versus that in normal cells) of these oncolytic agents. Both ONYX-201 and -203 contain seven single-base-pair mutations when compared with Ad5, four of which were common between ONYX-201 and -203. The mutation at nucleotide 8350, shared by both mutant viruses, was shown to be essential for the observed phenotypes. This mutation was mapped to the i-leader region of the major late transcription unit, resulting in the truncation of 21 amino acids from the C terminus of the i-leader protein. This work demonstrates that bioselection is a powerful tool for developing novel tumor-selective oncolytic viruses. Other potential applications of this technology are discussed.

Adenoviruses, Human↗