Cancer Genomics & Proteomics最新文献

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.

Background/aim: Circulating tumor DNA (ctDNA), which is shed from cancer cells into the bloodstream, offers a potential minimally invasive approach for cancer diagnosis and monitoring. This research aimed to assess the preoperative ctDNA levels in ovarian tumors patients' plasma and establish correlations with clinicopathological parameters and patient prognosis.

Patients and methods: Tumor DNA was extracted from ovarian tumor tissue from 41 patients. Targeted sequencing using a panel of 127 genes recurrently mutated in cancer was performed to identify candidate somatic mutations in the tumor DNA. SAGAsafe digital PCR (dPCR) assays targeting the candidate mutations were used to measure ctDNA levels in patient plasma samples, obtained prior to surgery, to evaluate ctDNA levels in terms of mutant copy number/ml and variant allele frequency.

Results: Somatic mutations were found in 24 tumor samples, 17 of which were from ovarian cancer patients. The most frequently mutated gene was TP53. Preoperative plasma ctDNA levels were detected in 14 of the 24 patients. With higher stage, plasma ctDNA mutant concentration increased (p for trend <0.001). The overall survival of cancer patients with more than 10 ctDNA mutant copies/ml in plasma was significantly worse (p=0.008).

Conclusion: Pre-operative ctDNA measurement in ovarian cancer patients' plasma holds promise as a predictive biomarker for tumor staging and prognosis.

Background/aim: Fucoxanthin (Fx), a dietary marine xanthophyll, exerts potent anticancer effects in various colorectal cancer (CRC) animal models. However, therapeutic effects of Fx in human cancer tissues remain unclear. A patient-derived xenograft (PDX) mouse model transplanted with cancer tissues from patients is widely accepted as the best preclinical model for evaluating the anticancer potential of drug candidates.

Materials and methods: Herein, we investigated the anticancer effects of Fx in PDX mice transplanted with cancer tissues derived from a patient with CRC (CRC-PDX) using LC-MS/MS- and western blot-based proteome analysis.

Results: The tumor in the patient with CRC was a primary adenocarcinoma (T3N0M0, stage II) showing mutations of certain genes that were tumor protein p53 (TP53), AT-rich interaction domain 1A (ARID1A), neuroblastoma RAS viral oncogene homolog (NRAS), and PMS1 homolog 2 (PMS2). Administration of Fx significantly suppressed the tumor growth (0.6-fold) and tended to induce differentiation in CRC-PDX mice. Fx up-regulated glycanated-decorin (Gc-DCN) expression, and down-regulated Kinetochore-associated protein DSN1 homolog (DSN1), phospho(p) focal adhesion kinase (pFAK)(Tyr³⁹⁷), pPaxillin(Tyr³¹), and c-MYC involved in growth, adhesion, and/or cell cycle, in the tumors of CRC-PDX mice than in control mice. Alterations in the five proteins were consistent with those in human CRC HT-29 and HCT116 cells treated with fucoxanthinol (FxOH, a major metabolite of Fx).

Conclusion: Fx suppresses development of human-like CRC tissues, especially through growth, adhesion, and cell cycle signals.

Background/aim: P21 is a cyclin-dependent kinase inhibitor regulating the cell cycle as a tumor suppressor. Using a p21 immunohistochemistry (IHC) assay, we compared tumor p21 levels with conventional clinico-pathological criteria in primary pancreatic endocrine tumor subsets with and without liver metastases.

Materials and methods: Sections from tissue microarray (TMA) including 13 archival metastatic primary and 18 non-metastatic primary pancreatic endocrine carcinomas/tumors (MP-PECAs/NMP-PETs) were stained with a monoclonal anti-p21^WAFI,CIP primary antibody. Tumor p21 IHCs were scored as the sum of intensity (0-3) and proportion scores (0-5) (Total Allred score: 0-8), and as p21% labelling index in the tumor. ROC curve analysis was used for most optimal p21 score cut-off (4 or >) and Fisher's exact test was used to compare the association among tumor p21 scores, conventional prognostic criteria, and liver metastases.

Results: For PET/PECA patients, mean ages were 55.6 years (27-73) and 49.3 years (28-71), M/F ratios were 7/11 and 7/6. Mean p21 labelling index (%) for MP- PECAs was 24% (range=3-63%) vs. 9% for NMP-PETs (range=1-25%) (p=0.022). The mean p21 index in MP-PECAs was significantly higher (24%) as compared to PIs (7%) (p=0.0047). Using a p21 Allred score of ≥4, high p21 IHC score had strong association with the presence of liver metastases (p-value <0.001). High tumor p21 IHC score had a 93% sensitivity, 68% specificity, 78% predictive accuracy, 66% positive, and 94% negative predictive values.

Conclusion: In patients with primary PETs, p21 IHC is superior to conventional criteria in predicting presence or absence of liver metastases.

Background/aim: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has a poor prognosis. Periodontitis, or tooth loss, is considered to be related to hepatocarcinogenesis and its poor prognosis. This study aimed to explore potential associations and cross-talk mechanisms between periodontitis and HCC.

Materials and methods: Periodontitis and HCC microarray datasets were acquired from the Gene Expression Omnibus (GEO) database and were analyzed to obtain differentially expressed (DE) lncRNAs, miRNAs and mRNAs. Functional enrichment analysis was used to detect the functions of these mRNAs. Then, a ceRNA network of periodontitis-related HCC was constructed. Least absolute shrinkage and selection operator (LASSO) regression, random forest algorithm, and support vector machine-recursive feature elimination (SVM-RFE) were performed to explore the diagnostic significance of mRNAs in periodontitis-related HCC. Cox regression analyses were conducted to screen mRNAs with prognostic significance in HCC. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) were conducted to validate the expression of these mRNAs in HCC tissues.

Results: A ceRNA network was constructed. Functional enrichment analysis indicated that the network is associated with immune and inflammatory responses, the cell cycle and liver metabolic function. LASSO, random forest algorithm and SVM-RFE showed the diagnostic significance of DE mRNAs in HCC. Cox regression analyses revealed that MSH2, GRAMD1C and CTHRC1 have prognostic significance for HCC, and qRT-PCR and IHC validated this finding.

Conclusion: Periodontitis may affect the occurrence of HCC by changing the immune and inflammatory response, the cell cycle and liver metabolic function. MSH2, GRAMD1C and CTHRC1 are potential prognostic biomarkers for HCC.

Hepatocellular carcinoma (HCC) ranges as number two with respect to the incidence of tumors and is associated with a dismal prognosis. The therapeutic efficacy of approved multi-tyrosine kinase inhibitors and checkpoint inhibitors is modest. Therefore, the identification of new therapeutic targets and entities is of paramount importance. We searched the literature for up-regulated circular RNAs (circRNAs) which mediate efficacy in preclinical in vivo models of HCC. Our search resulted in 14 circRNAs which up-regulate plasma membrane transmembrane receptors, while 5 circRNAs induced secreted proteins. Two circRNAs facilitated replication of Hepatitis B or C viruses. Three circRNAs up-regulated high mobility group proteins. Six circRNAs regulated components of the ubiquitin system. Seven circRNAs induced GTPases of the family of ras-associated binding proteins (RABs). Three circRNAs induced redox-related proteins, eight of them up-regulated metabolic enzymes and nine circRNAs induced signaling-related proteins. The identified circRNAs up-regulate the corresponding targets by sponging microRNAs. Identified circRNAs and their targets have to be validated by standard criteria of preclinical drug development. Identified targets can potentially be inhibited by small molecules or antibody-based moieties and circRNAs can be inhibited by small-interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) for therapeutic purposes.

Background/aim: Recent studies have demonstrated the crucial regulatory roles of circular RNAs (circRNAs) in cancer initiation and progression. The sponge mechanism of circRNAs has been shown to be widely active in various types of tumors. However, many circRNAs still have not been verified to function through this mechanism. This study aimed to investigate the regulatory mechanism of hsa_circ_0079557 in colorectal cancer (CRC) and its role in CRC progression.

Materials and methods: Raw gene expression profile datasets were downloaded from Gene Expression Omnibus (GEO) and combined to form a new dataset. Hsa_circ_0079557 was found to be highly expressed in CRC. Its role was evaluated in vitro and in vivo through a series of experiments, including quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry, colony formation, cell counting kit-8 (CCK-8), transwell assays, scratch wound healing assays, nude mice experiments, and immunohistochemistry (IHC). The association between hsa_circ_0079557 and the identified target microRNAs (miRNA) was confirmed through fluorescence in situ hybridization (FISH) and dual-luciferase reporter assays. The downstream target proteins were predicted using the web-based tool "TargetScan," and their expressions were determined using Western blot (WB).

Results: Hsa_circ_0079557 was found to be relatively up-regulated in CRC tissues and cell lines. Suppression of hsa_circ_0079557 expression inhibited cell proliferation in vitro and in vivo. Additionally, hsa_circ_0079557 acted as a "molecular sponge" for miR-502-5p, up-regulating the expression of Cyclin D1 (CCND1).

Conclusion: In this study, we identify a highly expressed circRNA in CRC and propose a novel pathway of hsa_circ_0079557/miR-502-5p/CCND1 in CRC.

Background/aim: The role of postoperative radiotherapy (RT) combined with chemotherapy (CT) for lymph node-positive (LN+) triple-negative breast cancer (TNBC) remains controversial. SUV39H1-mediated epigenetic regulation is associated with cancer cell migration, invasion, metastasis, and treatment resistance. This study aims to identify the role of SUV39H1 in TNBCs.

Materials and methods: Overall, 498 TNBCs with SUV39H1 RNA-seq profiles were retrieved from TCGA-BRCA and analyzed; the X-tile algorithm was used to stratify the population into low, intermediate, and high SUV39H1. Furthermore, we performed an in vitro clonogenic cell survival assay using the MDA-MB-231 cell line to assess the effects of SUV39H1 on cellular responses.

Results: The results showed that SUV39H1 was significantly higher in TNBC than normal tissue and luminal subtype breast cancer. Notably, SUV39H1 is significantly expressed in the basal-like 1 (BL1) and immunomodulatory (IM) subgroups, compared to other subtypes. Compared to patients with a low or medium expression of SUV39H1, omitting RT only worsens disease-free survival (DFS) in those with high SUV39H1 expression. The experimental results showed SUV39H1 was suppressed by si-SUV39H1, and SUV39H1 knockdown in MDA-MB-231-IV2-1 cells enhanced the cellular toxicity of doxorubicin and paclitaxel.

Conclusion: Targeting SUV39H1 may provide a potential guiding indication of omitting RT to avoid over-treatment and chemosensitivity for TNBC.