Cancer Genomics & Proteomics最新文献

Background/aim: Cervical cancer (CC) poses a significant threat to women's health and has a relatively poor prognosis due to local invasion and metastasis. It is, therefore, crucial to elucidate the molecular mechanisms of CC metastasis. SNHG3 has been implicated in various tumor metastasis processes, but its involvement in CC has not been thoroughly studied. Our study aimed to investigate the role of SNHG3 in metastasis and elucidate its underlying mechanisms in CC.

Materials and methods: LncRNA SNHG3 expression in CC tissues was analyzed using TCGA and GSE27469 databases. Normal cervical epithelial cells and CC cell lines were used to detect mRNA expression of SNHG3 via quantitative reverse transcription polymerase chain reaction (qRT-PCR). With RNA interference (RNAi) technology, antisense oligonucleotides (ASO) can act on HeLa cells to knockdown target gene expression. The influence of SNHG3 on cell migration and invasion were determined by wound healing and transwell assays. Transcriptome sequencing (RNA-seq) was used to seek abnormally expressed genes between SNHG3 knockdown cells and control cells. The expressions of epithelial-mesenchymal transition (EMT) and Wnt/β-catenin signaling related proteins were detected using western blot.

Results: SNHG3 was obviously up-regulated in CC tissues and cell lines, and ectopic expression of SNHG3 was associated with lymph node metastasis of CC. Knockdown of SNHG3 significantly inhibited cell migration and invasion in CC. Further molecular mechanism studies showed that SNHG3 knockdown could down-regulate the expression of WNT1 Inducible Signaling Pathway Protein 2 (WISP2) so as to inhibit the activation of the Wnt/β-catenin signaling pathway, and regulated the expression of EMT-related markers, that promoted the protein expression of E-cadherin, as well as decreased the expression of N-cadherin and vimentin.

Conclusion: SNHG3 appears to exert a pro-metastatic effect in CC, as evidenced by inhibition of cell migration and invasion upon SNHG3 knockdown. EMT also appears to be attenuated. Of interest is the down-regulation of WISP2 following SNHG3 knockdown leads to the inactivation of the Wnt/β-catenin signaling pathway.

Background/aim: Hepatocellular carcinoma (HCC) is a prevalent type of cancer worldwide. Although sorafenib is the only chemotherapy agent used for HCC, there is a need to discover a more potent anticancer agent with reduced side-effects. The compound, (S)-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (FMTC), was designed to inhibit tubulin assembly but its specific mechanisms of action have not been previously investigated. Herein, we investigated the regulation mechanisms by which FMTC affects the proliferation of the HCC cell line, Huh7.

Materials and methods: The effects of FMTC on cell viability and growth were analyzed in the HCC cell line, Huh7. Cell cycle and apoptosis regulated by FMTC were analyzed using flow cytometry. To verify the regulation of mRNA and protein expression of cell proliferation-related factors by FMTC in Huh7 cells, RT-qPCR and western blot analyses were employed.

Results: FMTC suppressed cell division dose-dependently by triggering cell cycle arrest at the G₂/M phase via p21 up-regulation. The increased phosphorylation of histone H3 on Ser-10 and the condensation of chromatin in FMTC-treated cells indicated mitotic arrest. Prolonged FMTC-induced cell cycle arrest triggered apoptosis.

Conclusion: FMTC inhibits the proliferation of human liver cancer cells by up-regulating p21, thereby inducing cell cycle arrest at the G₂/M phase. These findings highlight FMTC as a novel agent for HCC treatment.

Rapid advancements in high-throughput biological techniques have facilitated the generation of high-dimensional omics datasets, which have provided a solid foundation for precision medicine and prognosis prediction. Nonetheless, the problem of missing heritability persists. To solve this problem, it is essential to explain the genetic structure of disease incidence risk and prognosis by incorporating interactions. The development of the Bayesian theory has provided new approaches for developing models for interaction identification and estimation. Several Bayesian models have been developed to improve the accuracy of model and identify the main effect, gene-environment (G×E) and gene-gene (G×G) interactions. Studies based on single-nucleotide polymorphisms (SNPs) are significant for the exploration of rare and common variants. Models based on the effect heredity principle and group-based models are relatively flexible and do not require strict constraints when dealing with the hierarchical structure between the main effect and interactions (M-I). These models have a good interpretability of biological mechanisms. Machine learning-based Bayesian approaches are highly competitive in improving prediction accuracy. These models provide insights into the mechanisms underlying the occurrence and progression of complex diseases, identify more reliable biomarkers, and develop higher predictive accuracy. In this paper, we provide a comprehensive review of these Bayesian approaches.

Background/aim: One in two people will develop a tumor during their lifetime. Adenocarcinoma of the pancreas is one of the most aggressive types of cancer in humans with very poor long-term survival. A central role in the carcinogenesis of pancreatic cancer has been attributed to NFAT transcription factors. Previous studies have identified the transcription factor Sp1 as a binding partner of NFATc2 in pancreatic cancer. Using expression profile analysis, our group was able to identify the tumor necrosis factor TNFalpha as a target gene of the interaction between NFATc2 and Sp1. The present study investigated the effect of TNFalpha over-expression via the transcription factors NFATc2 and Sp1 on the pancreatic cancer cell lines PaTu 8988t and PANC-1.

Materials and methods: Transient transfection of NFATc2, Sp1, and TNFalpha siRNAs and their effects on the expression were investigated with immunoblot. Cell proliferation was measured with the ELISA BrdU assay. Cell migration was assayed with a Cell Migration Assay Kit using a Boyden chamber.

Results: Inhibition of the transfection factors NFATc2, Sp1, or TNFalpha by siRNA significantly inhibited proliferation, which was exacerbated when using the combination of NFATc2 and Sp1. TNFalpha was able to counterbalance this effect. In contrast to proliferation, migration of pancreatic cancer cells was increased by inhibiting these transfection factors.

Conclusion: Tumor progression is strongly influenced by transcriptional changes in signaling cascades and oncogene mutations as well as by changes in tumor suppressor genes. Further studies are needed to understand the underlying mechanisms of these processes.

Prostate cancer (PCa) is the second most common cancer in humans. Peptides have recently been used as targeted therapeutics in cancers, due to their extensive multi-functional applications. Two hypothalamic peptides, orexins A (OXA) and B (OXB) and their specific receptors, orexin receptor 1 (OX1R) and 2 (OX2R), orchestrate several biological processes in the central nervous system and peripheral organs. However, in addition to their role in physiological responses, orexins are involved in numerous inflammatory and/or neoplastic pathologies. The presence and expression of orexins in different cancer models, including prostate cancer, and their role in inducing pro- or anti-apoptotic responses in tumor cell lines, suggest that the orexinergic system might have potential therapeutic action or function as a diagnostic marker in PCa. In addition to the traditional animal models for studying human PCa, the canine model might also serve as an additional tool, due to its clinical similarities with human prostate cancer.

Background/aim: The fundamental and general hallmark of cancer cells, methionine addiction, termed the Hoffman effect, is due to overuse of methionine for highly-increased transmethylation reactions. In the present study, we tested if the combination efficacy of recombinant methioninase (rMETase) and a methionine analogue, ethionine, could eradicate osteosarcoma cells and down-regulate the expression of c-MYC.

Materials and methods: 143B osteosarcoma cells and Hs27 normal human fibroblasts were tested. The efficacy of rMETase alone and ethionine, alone and in their combination, on cell viability was determined with the WST-8 assay on 143B cells and Hs27 cells. c-MYC expression was examined with western immunoblotting and compared in 143B cells treated with/without rMETase, ethionine, or the combination of both rMETase and ethionine.

Results: 143B cells were more sensitive to both rMETase and ethionine than Hs 27 cells, with the following IC₅₀s: rMETase (143B: 0.22 U/ml; Hs27: 0.82 U/ml); ethionine (143B: 0.24 mg/ml; Hs27: 0.42 mg/ml). The combination of rMETase and ethionine synergistically eradicated 143B cells, lowering the IC50 for ethionine 14-fold compared to ethionine alone (p<0.001). In contrast, Hs27 fibroblasts were relatively resistant to the combination. The expression of c-MYC was significantly down-regulated only by the combination of rMETase and ethionine in 143B cells (p<0.001).

Conclusion: In the present study, we showed, for the first time, the synergistic combination efficacy of rMETase and ethionine on osteosarcoma cells in contrast to normal fibroblasts, which were relatively resistant. The combination of rMETase and ethionine down-regulated c-MYC expression in the cancer cells. The present results indicate the combination of rMETase and ethionine may reduce the malignancy of osteosarcoma cells and can be a potential future clinical strategy.

Background/aim: Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning protein (ARMS), is a transmembrane scaffold protein. Deregulated Kidins220 has been observed in various malignancies including melanoma, glioma, neuroblastoma, prostate cancer, pancreatic cancer, and ovarian cancer.

Materials and methods: In the current study, Kidins220 expression was determined at transcript and protein levels. A Kidins220 knockdown cell model was established to identify its role in cellular functions including cell cycle, proliferation, and invasion. Cell signalling was analysed by protein array and the TCGA gastric cancer cohort.

Results: Kidins220 transcript levels were significantly increased in gastric tumours, compared with adjacent normal tissues. More advanced tumours (TNMIII and TNMIV) exhibited higher protein levels of Kidins220 compared with early-stage tumours (TNMI and TNMII). Increased expression of Kidins220 in gastric cancer was associated with poorer overall survival. Loss of Kidins220 promoted cell invasion and adhesion of gastric cancer and correlated to epithelial-mesenchymal transition (EMT) and matrix metalloproteinase (MMP) signalling. Knockdown of Kidins220 promoted proliferation of gastric cancer cells with an increased population at the G₂/M phase.

Conclusion: Our study identified increased expression of Kidins220 in gastric cancer, which is associated with disease progression and poor prognosis. However, Kidins220 presented an inhibitory effect on the proliferation, invasion, and adhesion through a regulation of EMT, MMP and cell cycle.

Despite availability of several treatment options for non-small cell lung cancer (NSCLC), such as surgery, chemotherapy, radiation, targeted therapy and immunotherapy, the survival rate of patients for five years is in the range of 22%. Therefore, identification of new targets and treatment modalities for this disease is an important issue. In this context, we screened the PubMed database for up-regulated circular RNAs (circRNAs) which promote growth of NSCLC in preclinical models in vitro as well as in vivo xenograft models in immuno-compromised mice. This approach led to potential targets for further validation and inhibition with small molecules or antibody-derived entities. In case of preclinical validation, the corresponding circRNAs can be inhibited with small interfering RNAs (siRNA) or short hairpin RNAs (shRNA). The identified circRNAs act by sponging microRNAs (miRs) preventing cleavage of the mRNA of the corresponding targets. We identified nine circRNAs up-regulating transmembrane receptors, five circRNAs increasing expression of secreted proteins, nine circRNAs promoting expression of components of signaling pathways, six circRNAs involved in regulation of splicing and RNA processing, six circRNAs up-regulating actin-related and RNA processing components, seven circRNAs increasing the steady-state levels of transcription factors, two circRNAs increasing high-mobility group proteins, four circRNAs increasing components of the epigenetic modification system and three circRNAs up-regulating protein components of additional systems.

Background/aim: The treatment rate of Burkitt lymphoma (BL) is still low in low-income countries and among elderly patients. The c-Myc dysregulation induced by mutations is one of the characteristics of BL. However, studies on the downstream signaling pathways of c-Myc are still lacking. This study aimed to identify the signaling pathways regulated by c-Myc.

Materials and methods: Network and gene set analyses using c-Myc inhibition (i.e., c-Myc knock-down and c-Myc inhibitor treatment) transcriptome datasets for BL cell lines were performed to determine the pathways regulated by c-Myc. In addition, computational drug repurposing was used to identify drugs that can regulate c-Myc downstream signaling pathway.

Results: Computational drug repurposing revealed that the ERK/MAPK signaling pathway is regulated by c-Myc in BL and that this pathway can be modulated by vorinostat. Furthermore, in the pharmacogenomics database, vorinostat showed a cell viability half-maximal inhibitory concentration of less than 2 μM in the BL cell lines.

Conclusion: The downstream signaling pathway regulated by c-Myc and the drug that can modulate this pathway is presented for the first time.

Background/aim: Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide, with a high recurrence rate and a low cure rate. Phosphoglycerate kinase 1 (PGK1), an essential enzyme in the aerobic glycolysis pathway, is a prognostic marker for a variety of cancers. However, it remains unclear whether a PGK1-based immune signature can be used as a prognostic biomarker in HNSCC patients.

Materials and methods: We explored the potential oncogenic mechanisms of PGK1 by multiple bioinformatics analyses combined with multiple databases, including the correlation between PGK1 and prognosis, and the infiltration of immune cells in HNSCC. Functional enrichment analyses were further performed to investigate the potential role of PGK1 in HNSCC.

Results: The expression of PGK1 was significantly higher in HNSCC tissues compared to normal tissues. High expression of PGK1 was associated with poor prognosis in HNSCC, and multivariate cox regression analysis showed that PGK1 could be an independent prognostic factor in HNSCC. Pathway analysis revealed that PGK1 may regulate the pathogenesis of HNSCC through the immune signaling pathway. Moreover, PGK1 expression significantly correlated with the infiltration level of 16 types of immune cells.

Conclusion: The current study reports that PGK1 expression was increased in HNSCC and that high PGK1 expression was closely associated with poor prognosis and immune cell infiltration, which could serve as a promising independent prognostic biomarker and potential immunotherapeutic target for HNSCC.