TCGA-based analysis of oncogenic signaling pathways underlying oral squamous cell carcinoma

Background:Oral squamous cell carcinoma(OSCC)represents a prevalent malignancy in the oral and maxillofacial area,having a considerable negative impact on both the quality of life and overall survival of affected individuals.Our research endeavors to leverage bioinformatic approaches to elucidate oncogenic signaling pathways,with the ultimate goal of gaining deeper insights into the molecular underpinnings of OSCC pathogenesis,and thus laying the groundwork for the development of more effective therapeutic and preventive strategies.Methods:Differential expression analysis was performed on mRNA data from tumor and normal tissue groups to identify genes associated with OSCC,using The Cancer Genome Atlas database.Predictions of oncogenic signaling pathways linked to differentially expressedmRNAs were made,and these results were presented visually using R software,using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichments.Results:GO and KEGG analyses of 2938 differentially expressed genes in OSCC highlighted their significant involvement in various biological processes.Notably,these processes were related to the extracellular matrix,structural organization,connective tissue development,and cell cycle regulation.Conclusions:The comprehensive exploration of gene expression patterns provides valuable insights into potential oncogenic mechanisms in OSCC.

Significance of hepatitis virus infection in the oncogenicinitiation of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the most common causes of cancer-related death worldwide. Chronic infection of hepatitis B virus(HBV) and/or hepatitis C virus(HCV) is a major risk factor in the development of the HCC, independently from excessive alcohol abuse and metabolic disease. Since the biology of HBV and HCV is different, their oncogenic effect may go through different mechanisms, direct and/or indirect. Viral hepatitis infection is associated with cellular inflammation, oxidative stress, DNA damage, that may lead to subsequent hepatic injuries such as chronic hepatitis, fibrosis, cirrhosis, and finally HCC. Direct oncogenic properties of these viruses are related with their genotypic characteristics and the ability of viral proteins to interact with host proteins, thus altering the molecular pathways balance of the cells. In addition, the integration of HBV DNA, especially the gene S and X, in a particular site of the host genome can disrupt chromosomal stability and may activate various oncogenic mechanisms, including those in hematopoietic cells. Recently, several studies also had demonstrated that viral hepatitis could trigger the population of hepatic cancer stem cells. This review summarize available pre-clinical and clinical data in literature regarding oncogenic properties of HBV and HCV in the early initiation of HCC.

Isolation and Identification of a Specific cDNA Mapping to the Bam HI-I2 and -LFragments within the Inverted Repeats ofUnique Long Re-gion (IRL) in the Genom e ofMarek′s Disease Herpesvirus (MDV) Oncogenic Strain Beijing-1

Objective\ To understand the transcription of BamHI L DNA fragment from genome of strong virulent GA strain of Marek′s disease herpesvirus (MDV) in lymphoblastoid tumor tissue induced by oncogenic strain Beijing 1 (a specific local strain in China) of MDV. Methods\ Two oligonucleotide primers were synthesized according to the reported sequence of \%meq\% gene an ideal oncogenic candidate and our previously determined sequence of BamHI L fragment of Marek′s disease herpesvirus (MDV), respectively. Reverse transcriptase PCR(RT PCR) assay was performed by using these primers and the mRNA as a template which was isolated from visceral lymphoblastoid tumors obtained from chickens artificially infected with strain Beijing 1 of oncogenic MDV. Southern blot molecular hybridization was further carried out to detect the product of RT PCR with digoxigenin labeled nucleotide probe from BamHI I2 and L fragment in the gene library of MDV strain GA, respectively. Results\ Two probes could simultaneously hybridize this cDNA amplified by RT PCR with a length of about 730 bp. Conclusion\ It is suggested that \%meq\% transcription could extend from the right hand end of BamHI I2 to the adjacent BamHI L, and the BamHI L region was likely to be transcribed in MDV induced lymphoblastoid tumors.

Oncogenic fingerprint of epidermal growth factor receptor pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer

Epidermal growth factor receptor(EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer(CRC). Evidence from clinical trials indicates that cetuximab and panitumumab(antiEGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS(KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency. Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade. Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS, BRAF, PIK3CA and PTEN could be intrinsically resistant to EGFR blockade. Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients. While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC, further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.

Oncogenic role of Tc17 cells in cervical cancer development

BACKGROUND As one of the subsets of CD8+T cells,Tc17 cells have recently been identified and are characterized by the secretion of interleukin(IL)-17,which is related to inflammatory diseases.AIM To assess the status of Tc17 cells in cervical cancer and investigate the biological function of Tc17 cells in cervical cancer development.METHODS Flow cytometry assay,immunohistochemistry,and immunofluorescence were performed to detect the levels and phenotype of Tc17 cells in blood and tumor samples from patients with cervical cancer.Prior to cell suspension culture,ELISA was carried out to measure the production of IL-6,IL-1β,IL-23,CXCL12,and IL-17 in tumor tissue supernatant and co-cultured supernatant of patients with cervical cancer.In addition,multivariate analysis was performed to identify factors associated with overall survival using the Cox proportional hazards model.RESULTS Compared with normal tissues,Tc17 cells specifically accumulated in tumor tissues of cervical cancer patients.Cancer cells produced a greater amount of IL-6,IL-1β,and IL-23,which in turn promoted Tc17 cell polarization.Unlike the traditional cytotoxic CD8^+T cells,Tc17 cells secreted IL-17,which subsequently promoted CXCL12 expression in tumor cells,eventually enhancing the proliferation and migration of tumor cells.Thus,the ratio of tumor-infiltrating Tc17 cells was highly correlated with poor clinical outcome in patients with cervical cancer.CONCLUSION Our data identified the oncogenic role of Tc17 cells in the development of cervical cancer.We propose that the ratio of Tc17 cells may be a useful index in the prognosis of patients with cervical cancer.

ONCOGENIC TRANSFORMATION OF SYRIAN HAMSTER EMBRYO CELLS BY 5．3－MeV α PARTICLES AND A TUMOR PROMOTER PHORBOL ESTER

The primary Syrian hamster embryo(SHE) cells were used to study the oncogenic transformation by ￣(238)pu α particles or X-rays alone or in combination with a chemical promoter phorbol ester.Survival curves of SHE cells following exposure to α-particles or X-rays were fitted to single-or multi-target models,respectively. Model parameters were: Do = 0. 55 Gy. n = 1 for α particles 4 Do = 1.44 Gy. Dq = 3.0 Gy. n=7.7 for X-rays.Incidence of α particles or X-rays induced cell transformation was dose-dependant.α particles were more efficient in inducing cell transformation than that of X-rays. The enhancement of SHE cell transformation by phorbol 12-myristate 13-acetate(PMA) following exposure to α particles of 0. 25-1. 00 Gy was observed.

Prevalence and Genotype Distribution of Oncogenic-Risk Human Papilloma Virus in the Cervix of Climacteric Women with Normal Pap Smears

Objective: To find out the incidence of high-risk HPV infections on climacteric women within our area of influence;and to typify HPV genotypes on women with normal cytology that come to our hospitalary unit of menopausia. Material and Method: Cross-sectional study;with a random sample of 140 cases of climacteric women of ≥50 years of age, with normal Pap smears for the last 12 months. HPV determination was carried out by PCR for screening, and by hybrid capture for genotype typification. Results: The percentage of climacteric women who are carriers of oncogenic HPV and a normal Pap smear was of 11.43% (16/140 cases). The genotype found most frequently was HPV-16, followed by HPV-58, 51 and 18. Conclusions: We found a high prevalence of women who were carriers of oncogenic HPV in climacteric women with normal Pap smears (latent infections) in our health region. We consider that cervical cancer screening, either by PCR or conventional Pap smear, should not be minimized or ignored from 50 years of age onwards.

Oncogenic osteomalacia caused by a phosphaturic mesenchymal tumor of the femur: A case report

BACKGROUND Oncogenic osteomalacia caused by phosphaturic mesenchymal tumors is very difficult to detect.We report a case of tumor-induced osteomalacia caused by a phosphaturic mesenchymal tumor of the left femur in a middle-aged woman after medical imaging and biopsy.CASE SUMMARY A 57-year-old woman presented with progressive bone pain for five years.She was diagnosed with hypophosphatemic osteomalacia,as her laboratory data showed low serum phosphorus and low serum calcium.Her knee joint radiography revealed an osteolytic lesion of the left femur.A computed tomography scan showed mixed density shadows in the left femur.Magnetic resonance imaging of the left femur showed the presence of an oval area with a hypointense signal in T1-weighted magnetic resonance imaging(MRI)and highlow mixed signal in T2-weighted MRI.Biopsy samples revealed the presence of short spindle cells,vascularization,and characteristics of phosphaturic mesenchymal tumors.Tumor resection was performed,and the clinical presentations and laboratory abnormalities were reversed.CONCLUSION Diagnosis of oncogenic osteomalacia is difficult due to the varieties and localization of source tumors and absence of pathognomonic biomedical signs.Our case highlights the importance of a combination of medical imaging and biopsy in the diagnosis of oncogenic osteomalacia caused by a phosphaturic mesenchymal tumor.

ENHANCEMENT OF MORPHOLOGICAL AND ONCOGENIC TRANSFORMATION OF MOUSE CELLS WITH 12-O-TETRADECANOYL PHORBOL- 13-ACETATE FOLLOWING HERPES SINPLEX VIRUS TYPE 2 INFECTION

Sequential exposure of mouse embryo cells to HSV-2 and TPA gave rise to a synergistic enhancement of the transformation frequency. The transformants were selected for their ability to form dense foci of cells in medium containing 10% or 1%(low) fetal bovine serum. The average number of foci induced with HSV -2 followed by TPA was about 3 or 5(in low serum) fold greater than that induced with HSV- 2 alone. HSV- 2 antigen could be detected in about 10% of transformed cells before 27th passage with immunofluorescence technique. Of two cell lines established from single focus , one designated BL which was preferable to form foci in subcultures was tumorigenic after 21th passage. All of the tumors were sarcomas with interlacing bundles of pleomorphic fibroblasts. The other,designated NP was nontumorigenic until 50th passage. The BL cell line was composed of two distict cell types, i. e.,pigmented and unpigmented. No viral DNA sequences weredetected in the cells of tumors derived from BL cell line.

Genotypic Distribution of Different Variants of Oncogenic Human Papilloma Virus (HPV) among the Sexually Active HIV-1 Positive Female Population from Manipur, India

A total of 531 sexually active female populations from Manipur (north-eastern India), was chosen for this study. Out of 531 females from Manipur, 111 (20.9%) were HIV positive and 420 were HIV negative (79%). PCR amplification of the MY region of the HPV L1 gene using consensus MY09/11 primer showed 3.7% positivity in Manipur. Interestingly HPV infection among the HIV infected population from Manipur was found to be higher (9%) compared to the non HIV infected population from Manipur (3.7%). Further, single PCR for detecting the 16/18 genotypes and multiplex PCR for the other high risk groups showed equal prevalence of 16 and 18 and other high risk groups (1.3% each) in Manipur. This result was further confirmed by the sequencing and phylogenetic analysis. Thus, our study showed fairly high HPV prevalence rate among the HIV infected population compared to the non HIV cases in Manipur and also equal prevalence of 16/18 genotypes with other high risk groups. According to our knowledge this is the first kind of a genotypic study among the HPV-HIV co-infected population from northeastern states of India.

Disorder structural predictions of the native EWS and its oncogenic fusion proteins in rapport with the function

The Intrinsic structural disorder (ISD) of native EWS and its fusion oncogenic proteins, including EWS/FliI, EWS/ATF1 and EWS/ZSG, was estimated by different Predictors. The ISD difference between the wild type and the oncogenic fusions found in the CTD is due to the fusion partner, usually a transcription factor (TF). A disordered region was found in the sequence (AA 132 - 156) of the NTD (EAD) of EWS, consisting of the longest region free of Y motifs. The IQ domain (AA 258 - 280), a Y-free region, flanked by two Y-boxes, is also disordered by all used Predictors. The EWS functional regions RGG1, RGG2 and RGG3 are predominantly disordered. A strong dependence was found between the structure of EWS protein and its oncogenic fusions, and their estimated ISD. The oncogenic function of the fusions is related to a decreased ISD in the CTD, due to the fused TF. The Predictors shown that the different isoforms have similar profiles, shifted with some amino acids, due to the translocations. On the bases of the prediction results, an analysis was made of the EWS sequence and its functional regions with increased ISD to make a relationship sequence-disorder-function that could be helpful in the design of antitumor agents against the corresponding malignances.

Oncogenic Osteomalacia Associated with Phosphaturic Mesenchymal Tumor of the Knee: Case Presentation and Review of the Literature

Oncogenic osteomalacia (OOM) is an uncommon metabolic and bone disease caused by fibroblast growth factor 23 (FGF23), a phosphaturic factor produced by phosphaturic mesenchymal tumors (mixed connective tissue variant, PMTMCTV) characterized by phosphate leakage from kidneys and subsequent hypophosphatemia. In this paper, we present the case of a patient, 42-year-old woman affected by left side limp and pain involving lumbar spine, pelvis and hip joints, referred to the Rheumatology Department of our Hospital for the treatment of a suspected sero-negative spondilo-arthritis. During hospitalization patient began an immuno-suppressive therapy with TNF-alpha inhibitors associated with Pamidornate, Indometacin, Esomeprazole and vitamin D3. Nevertheless pain did not decrease and a new examination found a worst hypophosphatemia (1 mg/dl) with normal Ca and PTH’s plasma values. During the same check-up a painful bulge on the anterior part of the right knee was observed and the Magnetic Resonance Imaging scan revealed an ovular solid lesion in the soft tissue closed to the upper part of the patella. Histological analysis identified the lesion as a PMTMCTV. After surgical removal patient got complete recovery. We will discuss about diagnostic evaluation, differential diagnosis and treatment.

A potential oncogenic role of the commonly observed E2F5 overexpression in hepatocellular carcinoma

AIM: To explore the expression pattern of E2F5 in primary hepatocellular carcinomas (HCCs) and elucidate the roles of E2F5 in hepatocarcinogenesis. METHODS: E2F5 expression was analyzed in 120 primary HCCs and 29 normal liver tissues by immunohistochemistry analysis. E2F5-small interfering RNA was transfected into HepG2, an E2F5-overexpressed HCC cell line. After E2F5 knockdown, cell growth capacity and migrating potential were examined. RESULTS: E2F5 was significantly overexpressed in primary HCCs compared with normal liver tissues (P = 0.008). The E2F5-silenced cells showed significantly reduced proliferation (P = 0.004). On the colony formation and soft agar assays, the number of colonies was significantly reduced in E2F5-silenced cells (P = 0.004 and P = 0.009, respectively). E2F5 knockdown resulted in the accumulation of G0/G1 phase cells and a reduction of S phase cells. The number of migrating/invading cells was also reduced after E2F5 knockdown (P = 0.021). CONCLUSION: To our knowledge, this is the first evidence that E2F5 is commonly overexpressed in primary HCC and that E2F5 knockdown significantly repressed the growth of HCC cells.

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

A well-known tumor suppressor, p21, acts parado-xically by promoting tumor growth in some cellular conditions. These conflicting functions have been demonstrated in association with the HBx gene and in hepatocarcinogenesis. The molecular behavior of p21 depends on its subcellular localization. Nuclear p21 may inhibit cell proliferation and be proapoptotic, while cytoplasmic p21 may have oncogenic and anti-apoptotic functions. Because most typical tumor suppressive proteins also have different effects according to subcellular localization, elucidating the regulatory mechanisms underlying nucleo-cytoplasmic transport of these proteins would be significant and may lead to a new strategy for anti-hepatocellular carcinoma(HCC) therapy. Chromosome region maintenance 1(CRM1) is a major nuclear export receptor involved in transport of tumor suppressors from nucleus to cytoplasm. Expression of CRM1 is enhanced in a variety of malignancies and in vitro studies have shown the efficacy of specific inhibition of CRM1 against cancer cell lines. Interestingly, interferon may keep p21 in the nucleus; this is one of the mechanisms of its anti-hepatocarcinogenic function. Here we review the oncogenic property of p21, which depends on its subcellular localization, and discuss the rationale underlying a new strategy for HCC treatment and prevention.

Oncogenic activity of MCM7 transforming cluster

The miniature chromosome maintenance(MCM)complex is a group of proteins that are essential for DNA replication licensing and control of cell cycle progression from G1 to S phase.Recent studies suggest that MCM7 is overexpressed and amplified in a variety of human malignancies.MCM7 genome sequence contains a cluster of miRNA that has been shown to downregulate expression of several tumor suppressors including p21,E2F1,BIM and pTEN.The oncogenic potential of MCM7 and its embedded miRNA has been demonstrated vigorously in in vitro experiments and in animal models,and they appear to cooperate in initiation of cancer.MCM7 protein also serves as a critical target for oncogenic signaling pathways such as androgen receptor signaling,or tumor suppressor pathways such as integrinα7 or retinoblastoma signaling.This review analyzes the transforming activity and signaling of MCM7,oncogenic function of miRNA cluster that is embedded in the MCM7 genome,and the potential of gene therapy that targets MCM7.

Oncogenic driver mutations in non-small cell lung cancer: Past, present and future

Lung cancer,of which non-small lung cancer is the most common subtype,represents the leading cause of cancer related-death worldwide.It is now recognized that a significant proportion of these patients present alterations in certain genes that drive oncogenesis.In recent years,more of these so-called oncogenic drivers have been identified,and a better understanding of their biology has allowed the development new targeted agents.This review aims to provide an update about the current landscape of driver mutation in non-smallcell lung cancer.Alterations in Kirsten rat sarcoma,epidermal growth factor receptor,MET,anaplastic lymphoma kinase,c-ROS oncogene 1,v-raf murine sarcoma viral oncogene homolog B,neurotrophic receptor tyrosine kinase,human epidermal growth factor 2,neuregulin-1 and rearranged during transfection are discussed,as well as agents targeting these alterations.Current standards of treatment as well as promising future strategies are presented.Currently,more than fifteen targeted agents are food and Drug administration-approved for seven oncogenic drivers in non-small-cell lung cancer,highlighting the importance of actively searching for these mutations.Continuous and future efforts made in defining the biology of each of these alterations will help to elucidate their respective resistance mechanisms,and to define the best treatment strategy and therapeutic sequence.

Oncogenic role of microRNA-423-5p in hepatocellular carcinoma

BACKGROUND： It has been found that microRNA-423-5p （miR423-Sp） is an oncogenic factor and frequently upregulated in gastric carcinoma. However, the involvement of miR423- 5p in hepatocellular carcinoma （HCC） has been rarely reported. The aim of this study was to assess whether miR423-Sp is aberrantly expressed in HCC tissues, and to characterize its roles in the cancerous biology of HCC.

Oncogenic BRAF^(V600E) induces microglial proliferation through extracellular signal-regulated kinase and neuronal death through c-Jun N-terminal kinase

Activating V600E in v-Raf murine sarcoma viral oncogene homolog B(BRAF)is a common driver mutation in cancers of multiple tissue origins,including melanoma and glioma.BRAF^(V600E) has also been implicated in neurodegeneration.The present study aims to characterize BRAF^(V600E) during cell death and proliferation of three major cell types of the central nervous system:neurons,astrocytes,and microglia.Multiple primary cultures(primary cortical mixed culture)and cell lines of glial cells(BV2)and neurons(SH-SY5Y)were employed.BRAF^(V600E) and BRAF^(WT) expression was mediated by lentivirus or retrovirus.Blockage of downstream effectors(extracellular signal-regulated kinase 1/2 and JNK1/2)were achieved by siRNA.In astrocytes and microglia,BRAF^(V600E) induces cell proliferation,and the proliferative effect in microglia is mediated by activated extracellular signal-regulated kinase,but not c-Jun N-terminal kinase.Conditioned medium from BRAF^(V600E)-expressing microglia induced neuronal death.In neuronal cells,BRAF^(V600E) directly induces neuronal death,through c-Jun N-terminal kinase but not extracellular signal-regulated kinase.We further show that BRAF-related genes are enriched in pathways in patients with Parkinson’s disease.Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity.It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells.

Estrogen receptor beta suppresses the androgen receptor oncogenic effects in triple-negative breast cancer

Background:Triple-negative breast cancer(TNBC)is an aggressive type of breast cancer associated with poor prognosis and limited treatment options.The androgen receptor(AR)has emerged as a potential therapeutic target for luminal androgen receptor(LAR)TNBC.However,multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits.This study aimed to investigate the role of AR in TNBC and its detailed mechanism.Methods:Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4(NECTIN4)expression in TNBC tissues.Then,in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta(ERβ)in TNBC.Chromatin immunoprecipitation sequencing(ChIP-seq),co-immunoprecipitation(co-IP),molecular docking method,and luciferase reporter assay were performed to identify key molecules that affect the function of AR.Results:Based on the TNBC tissue array analysis,we revealed that ERβand AR were positive in 21.92%(32/146)and 24.66%(36/146)of 146 TNBC samples,respectively,and about 13.70%(20/146)of TNBC patients were ERβpositive and AR positive.We further demonstrated the pro-tumoral effects of AR on TNBC cells,however,the oncogenic biology was significantly suppressed when ERβtransfection in LAR TNBC cell lines but not in AR-negative TNBC.Mechanistically,we identified that NECTIN4 promoter–42 bp to–28 bp was an AR response element,and that ERβinteracted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial–mesenchymal transition in tumor progression.Conclusions:This study suggests that ERβfunctions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation.Therefore,our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.

Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia

With the support of the National Natural Science Foundation of China and the Chinese Academy of Sciences,the laboratory led by Yang CaiGuang(杨财广)from Shanghai Institute of Materia Medica,Chinese Academy of Sciences,has identified a potential therapeutic small molecule for treating the acute myeloid leukemia(AML)by targeting the oncogenic RNA demethylase FTO,which was published in Figure Schematic diagram of small-molecular targeting of the oncogenic FTO demethylase.Cancer Cell(2019,35:677—691).