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International audience; Mammalian cells integrate different types of stimuli that govern their fate. These stimuli encompass biochemical as well as biomechanical cues (shear, tensile, and compressive stresses) that are usually studied separately. The phosphatidylinositol 3-kinase (PI3K) enzymes, producing signaling phosphoinositides at plasma and intracellular membranes, are key in intracellular signaling and vesicular trafficking pathways. Recent evidence in cancer research demonstrates that these enzymes are essential in mechanotransduction. Despite this, the importance of the integration of biomechanical cues and PI3K-driven biochemical signals is underestimated. In this opinion article, we make the hypothesis that modeling of biomechanical cues is critical to understand PI3K oncogenicity. We also identify known/missing knowledge in terms of isoform specificity and molecular pathways of activation, knowledge that is needed for clinical applications.

Deregulation of the epigenome underlies oncogenesis in numerous primary brain tumours in children and young adults. In this review, we describe how recurrent mutations in isocitrate dehydrogenases or histone 3 variants (oncohistones) in gliomas, expression of the oncohistone mimic enhancer of Zeste homologs inhibiting protein (EZHIP) in a subgroup of ependymoma, and epigenetic alterations in other embryonal tumours promote oncogenicity. We review the proposed mechanisms of cellular transformation, current tumorigenesis models and their link to development. We further stress the narrow developmental windows permissive to their oncogenic potential and how this may stem from converging effects deregulating polycomb repressive complex (PRC)2 function and targets. As altered chromatin states may be reversible, improved understanding of aberrant cancer epigenomes could orient the design of effective therapies.

Human papilloma virus genotype 16 (HPV-16), a predominant etiological cause of cervical cancer (CC) vary in inflicting oncogenicity according to their geographical distribution and mutational changes. With no published data from central India, the present study aimed to genetically analyze HPV-16 E6/E7 variant obtained from CC women of Chhattisgarh. In twenty one CC patients, PCR amplified E6/E7 genes were decoded by DNA sequencing to study phylogenetic relatedness, mutational changes and their in-silico effect on protein structure. E6 analysis revealed nineteen sequences exhibited intratypic variation. L83V mutation was observed in 76.2% sequences followed by S71C seen in 28.6% sequences. Mutations of E41G, A46G, F47V, R77S, L99V and Q107K were observed in three sequences each. C140 Stop codon mutation has caused early truncation of E6 in three sequences to produce the conformational structural change. In contrast, E7 was relatively more conserved showing D4E (4.7%), G88R (23.8%), I93T (9.5%) and C94S (9.5%) mutations. Other than L83V and S71C, E6 and E7 mutations were reported for the first time from India. E6/E7 nonsynonmous mutations have a spectrum of biological effect in progression of CC. Phylogenetic analysis revealed ten sequence belonged to Asian while eleven to European sublineage to show CC cases in Chhattisgarh are a mix of Asian and European lineage. Asian sequences showing higher frequency of L83V mutations and exclusive presence of S71C and C140 Stop codon mutations may be linked with higher oncogenicity. Various E6/E7 mutational data may prove useful for development of better diagnostic and vaccine for the region of Chhattisgarh.

L-type amino acid transporter 1 (LAT1)/SLC7A5 is the first identified CD98 light chain disulfide linked to the CD98 heavy chain (CD98hc/SLC3A2). LAT1 transports large neutral amino acids, including leucine, which activates mTOR, and is highly expressed in human cancers. We investigated the oncogenicity of human LAT1 introduced to NIH/3T3 cells by retrovirus infection. NIH/3T3 cell lines stably expressing human native (164C) or mutant (164S) LAT1 (naLAT1/3T3 or muLAT1/3T3, respectively) were established. We confirmed that endogenous mouse CD98hc forms a disulfide bond with exogenous human LAT1 in naLAT1/3T3, but not in muLAT1/3T3. Endogenous mouse CD98hc mRNA increased in both naNIH/3T3 and muLAT1/3T3, and a similar amount of exogenous human LAT1 protein was detected in both cell lines. Furthermore, naLAT1/3T3 and muLAT1/3T3 cell lines were evaluated for cell growth-related phenotypes (phosphorylation of ERK, cell-cycle progression) and cell malignancy-related phenotypes (anchorage-independent cell growth, tumor formation in nude mice). naLAT1/3T3 had stronger growth- and malignancy- related phenotypes than NIH/3T3 and muLAT1/3T3, suggesting the oncogenicity of native LAT1 through its interaction with CD98hc. Anti-LAT1 monoclonal antibodies significantly inhibited in vitro cell proliferation and in vivo tumor growth of naLAT1/3T3 cells in nude mice, demonstrating LAT1 to be a promising anti-cancer target.

BACKGROUND Glioblastoma (GBM) is one of the most common primary brain tumors, which accounts up to 80% of malignant brain tumors and the 5-year relative survival rate is below 5%. Recent studies showed that the lipid metabolism played an essential role in GBM development. As a peroxisome proliferators-activated receptors γ (PPAR-γ) agonist, telmisartan improves the lipid metabolism and has been used to treat hypertension for long time. It has also been shown to have anticancer function, such as in lung cancer and melanoma. METHODS Incucyte real-time live cell imaging system was used to assess the effect of telmisartan on glioma cell lines U87 and U251 proliferation. Transwell assay and colony formation assay were conducted to detect the effect of telmisartan on oncogenicity of GBM cell lines. Western blot and immunofluorescence analysis were used to detect the effect of telmisartan on the expression of PPAR-γ and hydroxyacyl-coenzyme A dehydrogenase alpha subunit (HADHA). RESULTS We demonstrate that telmisartan inhibits two glioma cell lines U87 and U251 proliferation in a time- and dose-dependent manner, and arrests the cell cycle at S phase. We further show that telmisartan decreases the oncogenicity of GBM cell lines. Our data show that telmisartan treatment significantly increases the PPAR-γ expression level, enhances the lipid oxidation, and upregulates the level of fatty acid oxidation key enzyme HADHA. CONCLUSIONS Telmisartan inhibits the proliferation and oncogenicity while it also increases the lipid oxidation of human GBM cells.

Multiple Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M (Palm M) block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared with Palm M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MAP kinase kinase (MEK) inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes as regulators of the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers.

The DDR is a complex signaling network responsible for the preservation of genomic integrity. Beta human papillomaviruses (β-HPVs) are able to destabilize the host genome by attenuating the DDR machinery at the molecular scale following expression of the oncogenes E6 and E7. In the event of β-HPV infection, the E6- and E7-mediated inhibition of the DDR enhances the oncogenicity of UV-induced mutations to enable carcinogenesis in an otherwise immunocompetent host, marking an important mechanistic divergence from the alpha genus of HPVs. In this review, we summarize recent updates to build upon the ‘hit-and-run’ hypothesis of β-HPV pathomechanism and highlight strain-dependent variations. Simultaneously, we illuminate points within the β-HPV–DDR interface that may unravel new insights for HPV viral genetics, genus-specific mechanistic models, and developments in targeted molecular therapy of β-HPV-related cancers.

Background and AimsHepatoblastoma (HB), the most common pediatric liver cancer, often bears β-catenin mutations and deregulates the Hippo tumor suppressor pathway. Murine HBs can be generated by co-expressing β-catenin mutants and the constitutively active Hippo effector YAPS127A. Some HBs and other cancers also express mutants of NFE2L2/NRF2 (NFE2L2), a transcription factor that tempers oxidative and electrophilic stress. In doing so, NFE2L2 either suppresses or facilitates tumorigenesis.MethodsWe evaluated NFE2L2’s role in HB pathogenesis by co-expressing all combinations of mutant β-catenin, YAPS127A and the patient-derived NFE2L2 mutants L30P and R34P in murine livers. We evaluated growth, biochemical and metabolic profiles and transcriptomes of the ensuing tumors.ResultsIn association with β-catenin+YAPS127A, L30P and R34P markedly accelerated HB growth and generated widespread cyst formation and necrosis, which are otherwise uncommon features. Surprisingly, any two members of the mutant β-catenin-YAPS127A-L30P/R34P triad were tumorigenic, thus directly establishing NFE2L2’s oncogenicity. Each tumor group displayed distinct features but shared 22 similarly deregulated transcripts, 10 of which perfectly correlated with survival in human HBs and 17 of which correlated with survival in multiple adult cancers. One highly up-regulated transcript encoded serpin E1, a serine protease inhibitor that regulates fibrinolysis, growth and extracellular matrix. The combination of mutant β-catenin, YAPS127A and Serpin E1, while not accelerating cystogenic tumor growth, did promote the wide-spread necrosis associated with mutant β-catenin-YAPS127A-L30P/R34P tumors.ConclusionsOur findings establish the direct oncogenicity of NFE2L2 mutants and key transcripts, including serpin E1, that drive specific HB features.

Gene fusions involving the neurotrophic receptor tyrosine kinase genes NTRK1, NTRK2, and NTRK3, are well established oncogenic drivers in a broad range of pediatric and adult tumors. These fusions are also important actionable markers, predicting often dramatic response to FDA approved kinase inhibitors. Accurate interpretation of the clinical significance of NTRK fusions is a high priority for diagnostic laboratories, but remains challenging and time consuming given the rapid pace of new data accumulation, the diversity of fusion partners and tumor types, and heterogeneous and incomplete information in variant databases and knowledgebases. The ClinGen NTRK Fusions Somatic Cancer Variant Curation Expert Panel (SC-VCEP) was formed to systematically address these challenges and create an expert-curated resource to support clinicians, researchers, patients and their families in making accurate interpretations and informed treatment decisions for NTRK fusion-driven tumors. We describe a system for NTRK fusion interpretation (including compilation of key elements and annotations) developed by the NTRK fusions SC-VCEP. We illustrate this stepwise process on examples of LMNA::NTRK1 and KANK1::NTRK2 fusions. Finally, we provide detailed analysis of current representation of NTRK fusions in public fusion databases and the CIViC knowledgebase, performed by the NTRK fusions SC-VCEP to determine existing gaps and prioritize future curation activities.

MicroRNAs (miRNAs) are emerging biomarkers in biological processes and the role of miR‐495‐3p has been identified in melanoma, while the detailed molecular mechanisms remain to be further explored. We aim to explore the effect of histone deacetylase 3 (HDAC3) and miR‐495‐3p on epithelial‐mesenchymal transition (EMT) and oncogenicity of melanoma cells by regulating tumour necrosis factor receptor‐associated factor 5 (TRAF5). Levels of HDAC3, miR‐495‐3p and TRAF5 in melanoma tissues and pigmented nevus tissues were determined, and the predictive roles of HDAC3 and miR‐495‐3p in prognosis of melanoma patients were measured. The melanoma cells were screened and transfected with relative oligonucleotides and plasmids, and the expression of HDAC3, miR‐495‐3p and TRAF5, and phenotypes of melanoma cells were gauged by a series of assays. The relations between HDAC3 and miR‐495‐3p, and between miR‐495‐3p and TRAF5 were confirmed. HDAC3 and TRAF5 were increased while miR‐495‐3p was decreased in melanoma cells and tissues, and the low expression of miR‐495‐3p as well as high expression of HDAC3 indicated a poor prognosis of melanoma patients. Inhibited HDAC3 elevated miR‐495‐3p to suppress EMT and oncogenicity of melanoma cells by reducing TRAF5. HDAC3 particularly bound to miR‐495‐3p and TRAF5 was the target gene of miR‐495‐3p. Our results revealed that down‐regulated HDAC3 elevates miR‐495‐3p to suppress malignant phenotypes of melanoma cells by inhibiting TRAF5, thereby repressing EMT progression of melanoma cells. This study may provide novel targets for melanoma treatment.

PIK3CA hotspot mutation is well established as an oncogenic driver event in cancer and its durable and efficacious inhibition is a focus in the development and testing of clinical cancer therapeutics. However, hundreds of cancer-associated PIK3CA mutations remain uncharacterized, their sensitivity to PI3K inhibitors unknown. Here, we describe a series of PIK3CA C-terminal mutations, primarily nucleotide insertions, that produce a frame-shifted protein product with an extended C terminus. We report that these mutations occur at a low frequency across multiple cancer subtypes, including breast, and are sufficient to drive oncogenic transformation in vitro and in vivo. We demonstrate that the oncogenicity of these mutant p110α proteins is dependent on p85 but not Ras association. P110α-selective pharmacologic inhibition blocks transformation in cells and mammary tumors characterized by PIK3CA C-terminal mutation. Taken together, these results suggest patients with breast and other tumors characterized by PIK3CA C-terminal frameshift mutations may derive benefit from p110α-selective inhibitors, including the recently FDA-approved alpelisib.

Purpose: We pursued genomic analysis of an exceptional responder with non–small cell lung cancer (NSCLC) through a multi-platform effort to discover novel oncogenic targets. Experimental Design: In this open-label, single-arm phase II study (NCT01829217), an enriched cohort of patients with advanced NSCLC was treated with the multi-kinase inhibitor sunitinib. The primary endpoint was objective response rate. Tissue was collected for multi-platform genomic analysis of responders, and a candidate oncogene was validated using in vitro models edited by CRISPR-Cas9. Results: Of 13 patients enrolled, 1 patient (8%), a never smoker, had a partial response lasting 33 months. Genomic analysis of the responder identified no oncogenic variant using multi-platform DNA analysis including hotspot allelotyping, massively parallel hybrid-capture next-generation sequencing, and whole-exome sequencing. However, bulk RNA-sequencing (RNA-seq) revealed a novel fusion, TMEM87A–RASGRF1, with high overexpression of the fusion partners. RASGRF1 encodes a guanine exchange factor which activates RAS from GDP-RAS to GTP-RAS. Oncogenicity was demonstrated in NIH/3T3 models with intrinsic TMEM87A–RASGRF1 fusion. In addition, activation of MAPK was shown in PC9 models edited to express this fusion, although sensitivity to MAPK inhibition was seen without apparent sensitivity to sunitinib. Conclusions: Sunitinib exhibited limited activity in this enriched cohort of patients with advanced NSCLC. Nonetheless, we find that RNA-seq of exceptional responders represents a potentially underutilized opportunity to identify novel oncogenic targets including oncogenic activation of RASGRF1.

MicroRNAs (miRNAs) act as crucial regulators of biological pathways/processes by reinforcing transcriptional programs and moderating transcripts. Emerging evidences have shown the involvement of dysregulated miRNAs in pathophysiology of human diseases including several cancer types. Recently, miR-197-3p has been reported to play different roles in different cancers; however, its role in fibrosarcoma, a highly aggressive and malignant soft tissue sarcoma originated from the mesenchymal tissues, has not yet been studied. Therefore, this study aims to investigate the possible regulatory roles of miR-197-3p in the oncogenicity of fibrosarcoma. For this, we initially performed qRT-PCR of miR-197-3p, which we found to be downregulated in HT1080 human fibrosarcoma cells compared with IMR90-tert normal fibroblast cells. Subsequently, we performed gain-of-function study by employing several methods such as MTT assay, clonogenic assay, wound healing, flow cytometry cell cycle analysis, and acridine orange staining after transfecting HT1080 cells with miR-197-3p mimic. From these assays, we observed that miR-197-3p significantly inhibits viability, colony forming, and migration ability as well as triggers G2/M phase cell cycle arrest and autophagy in fibrosarcoma cells. To understand the mechanism through which miRNA performs these functions, we predicted its targets using TargetScan and performed pathway enrichment analysis after screening them by their expression in fibrosarcoma. Among the enriched targets, we found RAN (ras-related nuclear protein) to be a crucial target through which miR-197-3p represses tumorigenesis by binding to its 3´ UTR, validated by luciferase reporter assay. The tumor suppressive role of the miRNA was further confirmed by transfecting its mimic in RAN-overexpressed cells which showed significant attenuation in tumorigenic effect of RAN in fibrosarcoma as seen in different assays. Taken together, our study unveiled that miR-197-3p acts as an oncosuppressor in fibrosarcoma through G2/M phase arrest and induction of autophagy, and raises the possibility to act as a novel therapeutic intervention for the malignancy.

Sporadic reports have described cancer cases in which multiple driver mutations (MMs) occur in the same oncogene1,2. However, the overall landscape and relevance of MMs remain elusive. Here we carried out a pan-cancer analysis of 60,954 cancer samples, and identified 14 pan-cancer and 6 cancer-type-specific oncogenes in which MMs occur more frequently than expected: 9% of samples with at least one mutation in these genes harboured MMs. In various oncogenes, MMs are preferentially present in cis and show markedly different mutational patterns compared with single mutations in terms of type (missense mutations versus in-frame indels), position and amino-acid substitution, suggesting a cis-acting effect on mutational selection. MMs show an overrepresentation of functionally weak, infrequent mutations, which confer enhanced oncogenicity in combination. Cells with MMs in the PIK3CA and NOTCH1 genes exhibit stronger dependencies on the mutated genes themselves, enhanced downstream signalling activation and/or greater sensitivity to inhibitory drugs than those with single mutations. Together oncogenic MMs are a relatively common driver event, providing the underlying mechanism for clonal selection of suboptimal mutations that are individually rare but collectively account for a substantial proportion of oncogenic mutations. Analysis of genomic data from more than 60,000 cancer samples uncovers frequent multiple driver mutations in individual oncogenes, which confer enhanced oncogenicity in combination.

2-[8-Arylmethylidenhydrazino-3-methyl-7-(1-oxothietan-3-yl)xanthin-1-yl]ethyl acetates ( IV ) were synthesized via the reactions of ethyl 2-[8-hydrazino-3-methyl-7-(1-oxothietan-3-yl)xanthin-1-yl]acetate ( III ) with various benzaldehydes and acetophenones. The chemical structures of compounds were elucidated by IR and NMR spectroscopy and elemental analyses. Studies in vitro and on laboratory animal used to evaluate antiplatelet, anticoagulant, antioxidant and anti-inflammatory activity have revealed promising compounds exhibiting antiplatelet (hydrazone IVd) and antioxidant (hydrazone IVb ) properties. According to in silico calculations, both compounds IVb and IVd are characterized by the absence of toxic risks (mutagenicity, oncogenicity, reproductive toxicity, and local irritating effects) and have acceptable topological polar surface area (TPSA). Therefore, these compounds are promising for further investigation.

Background/aim Cervical cancer is one of the most common cancers worldwide and a major cause of cancer-related mortality among women. Previous studies have reported that microRNA-miR-187*, which is one of the non-coding parts of the genome producing small conserved ribonucleic acids, is associated with various cancers. In this study, we explored the function of miR-187* in cervical cancer cells. Materials and methods miR-187* mimic, WWOX reporter constructs, siRNA and overexpression constructs were transfected into SiHa cells to investigate the function and regulatory mechanisms of miR-187*. Results Exogenous miR-187* was found to increase the oncogenic phenotypes of SiHa cells. The tumor suppressor gene WWOX is a novel target of miR-187* in SiHa cells. WWOX siRNA suppressed endogenous WWOX expression and increased the oncogenic phenotypes of SiHa cells. Exogenous WWOX expression was able to suppress the oncogenic phenotypes of SiHa cells and rescue cells from miR-187*-induced migration. Conclusion miR-187* seems to enhance SiHa cervical cancer cell oncogenicity via suppression of the WWOX pathway.

Long non-coding RNA termed GAS6 antisense RNA 1 (GAS6-AS1) plays an essential role in gastric and non-small cell lung cancers. Nonetheless, the function of GAS6-AS1 in hepatocellular carcinoma (HCC...

Gain-of-function (GOF) p53 mutations occur commonly in human cancer and lead to both loss of p53 tumor suppressor function and acquisition of aggressive cancer phenotypes. The oncogenicity of GOF mutant p53 is highly related to its abnormal protein stability relative to wild type p53, and overall stoichiometric excess. We provide an overview of the mechanisms of dysfunction and abnormal stability of GOF p53 specifically in lung cancer, the leading cause of cancer-related mortality, where, depending on histologic subtype, 33-90% of tumors exhibit GOF p53 mutations. As a distinguishing feature and oncogenic mechanism in lung and many other cancers, GOF p53 represents an appealing and cancer-specific therapeutic target. We review preclinical evidence demonstrating paradoxical depletion of GOF p53 by proteasome inhibitors, as well as preclinical and clinical studies of proteasome inhibition in lung cancer. Finally, we provide a rationale for a reexamination of proteasome inhibition in lung cancer, focusing on tumors expressing GOF p53 alleles.

During the last years a considerable therapeutic progress in melanoma patients with the RAF V600E mutation via RAF/MEK pathway inhibition and immuno-therapeutic modalities has been witnessed. However, the majority of patients relapse after therapy. Therefore, a deeper understanding of the pathways driving oncogenicity and metastasis of melanoma is of paramount importance. In this review, we summarize microRNAs modulating tumor growth, metastasis, or both, in preclinical melanoma-related in vivo models and possible clinical impact in melanoma patients as modalities and targets for treatment of melanoma. We have identified miR-199a (ApoE, DNAJ4), miR-7-5p (RelA), miR-98a (IL6), miR-219-5p (BCL2) and miR-365 (NRP1) as possible targets to be scrutinized in further target validation studies.

Human papillomavirus 16 (HPV16) infection is the aetiologic factor for the development of cervical dysplasia and is regarded as highly carcinogen, because it is implicated in more than 50% of cervical cancer cases, worldwide. The tumourigenic potential of HPV16 has triggered the extensive sequence analysis of viral genome in order to identify nucleotide variations and amino acid substitutions that influence viral oncogenicity and subsequently the initiation and progression of cervical cancer. Nowadays, specific mutations of HPV16 DNA have been associated with an increased risk of high-grade squamous intraepithelial lesions and invasive cervical cancer (ICC) development, including E6 : Q14H, H78Y, L83V, Ε7 : N29S, S63F, E2 : H35Q, P219S, T310K, E5 : I65V, whereas highly conserved regions of viral DNA have been extensively characterised. In addition, numerous novel HPV16 mutations are observed among the studied populations from various geographic regions, hence advocating that different HPV16 strains seem to emerge with different tumourigenic capacities. The present review focuses on the variability of the early genes and the long control region, emphasising on the association of specific mutations with the development of severe dysplasia. Finally, it evaluates whether specific regions of HPV16 DNA are able to serve as valuable biomarkers for cervical cancer risk.

Increasing evidence suggested that cholesterol is an important integrant of cell membranes, that plays a key role in tumor progression, immune dysregulation, and pathological changes in epigenetic mechanisms. Based on these theories, there is a growing interest on targeting cholesterol in the treatment of cancer. Here, we comprehensively reviewed the major function of cholesterol on oncogenicity, the therapeutic targets of cholesterol and its metabolites in cancer, and provide detailed insight into the essential roles of cholesterol in mediating immune and epigenetic mechanisms of the tumor microenvironment. It is also worth mentioning that the gut microbiome is an indispensable component of cancer mediation because of its role in cholesterol metabolism. Finally, we summarized recent studies on the potential targets of cholesterol and their metabolism, to provide more therapeutic interventions in oncology.

High risk human papillomavirus (HPV) infections induce squamous epithelial tumors in which the virus replicates. Initially, the virus-infected epithelial cells are untransformed, but expand in both number and area at the expense of normal squamous epithelial cells. How this occurs is unknown, but is presumed to be due to viral oncogene expression. We have developed an in vitro assay in which colonies of post-confluent HPV16 expressing cells outcompete confluent surrounding normal keratinocytes for surface area. The enhanced cell competition induced by the complete HPV16 genome is conferred by E6 expression alone, and not by individual expression of E5 or E7. In traditional oncogene assays, E7 is a more potent oncogene than E6, but such assays do not include interaction with normal surrounding cells. These new results separate classic oncogenicity that is primarily conferred by E7, from cell competition that we show is primarily conferred by E6, and provides a new biological role for E6 oncoproteins from high risk human papillomaviruses.ImportanceHigh risk papillomavirus infections induce epithelial tumors, some of which evolve into malignancies. The development and maintenance of cancer is due to the virally encoded E6 and E7 oncoproteins. How a virally infected keratinocyte out-competes normal uninfected keratinocytes has been unknown. The present work shows that the enhanced competition of HPV16-infected cells is primarily due to the expression of the E6 oncoprotein and not the E7 or E5 oncoproteins. This work shows the importance of measuring oncoprotein traits in the context of cell competition with uninfected cells, and shows the potential of papillomavirus oncoproteins to be novel genetic probes for the analysis of cell competition.

Protein tyrosine kinase 7 (PTK7), a catalytically defective receptor protein tyrosine kinase (RPTK), plays an oncogenic role by activating an unidentified TKI-258 (dovitinib)-sensitive RPTK in esophageal squamous cell carcinoma (ESCC) cells. Here, we demonstrate that among TKI-258–sensitive RPTKs, fibroblast growth factor receptor (FGFR) 1 is significantly up-regulated in ESCC tissues and cell lines. We show that PTK7 colocalizes with FGFR1 and binds it via its extracellular domain in human embryonic kidney 293 and ESCC TE-10 cells. PTK7 knockdown not only reduced ligand-free and fibroblast growth factor (FGF)-induced phosphorylation of FGFR1 but also the interaction of signaling adaptor proteins with FGFR1 and activation of downstream signaling proteins in TE-10 cells. In addition, PTK7 knockdown reduced FGF-induced oncogenic phenotypes including proliferation, anchorage-independent colony formation, wound healing, and invasion in ESCC cells. Taken together, our data demonstrate that PTK7 binds and activates FGFR1 independent of FGF and thus increases oncogenicity of PTK7- and FGFR1-positive cancers such as ESCC.—Shin, W.-S., Lee, H. W., Lee, S.-T. Catalytically inactive receptor tyrosine kinase PTK7 activates FGFR1 independent of FGF.

Avian leukosis virus subgroup J has been found to infect many types of chickens with various genetic backgrounds. The ALV-J strain NX0101, which was isolated from broiler breeders in 2001, mainly induces the formation of myeloid cell tumors. However, strain HN10PY01, which was recently isolated from laying hens, mainly induces the formation of myeloid cell tumors and hemangioma. In order to determine the difference in pathogenicity of the 2 strains in broiler chickens, 2 groups of chicken embryos were infected with NA0101 and HN10PY01 separately. A comparison was made of the mortality, oncogenicity, body weights, indexes for immune organs, levels of ALV group-specific antigen p27, and mRNA expression levels of the tumor-related gene, p53, in ALV-J-infected birds and immune organs of theses chickens in response to Newcastle Disease Virus (NDV) and avian influenza virus subtype H9 (AIV-H9) vaccination. The results indicated that strain NX0101 was highly pathogenic in broiler chickens and led to a 30% mortality rate and 45% oncogenicity, compared with the HN10PY01-infected birds. Weight of chickens was also significantly lower after 15 wk (P < 0.05). In addition, the mRNA expression levels of tumor-related p53 in medulla, liver, and lung in broilers infected with strain NX0101 were significantly higher than those infected with strain HN10PY01 (P < 0.05). These results indicated that strain NX0101 had a higher replication ability in broiler chickens. The findings of this study will contribute to further elucidating the mechanisms underlying host susceptibility and tumor classification in ALV-J-infected chickens.

Human papillomavirus (HPV) infection contributes to virtually all cases of cervical cancer, the fourth most common cancer affecting women worldwide. The oncogenicity of HPV is mainly attributable to the E6 and E7 oncoproteins. HPV-52 is the seventh most common HPV type globally, but it has a remarkably high prevalence in East Asia. In previous studies it has been speculated that the oncogenicity might vary among different HPV-52 variants. In the present study, we compared the oncogenicity of E6 derived from the HPV-52 prototype and three commonly found variants, V1 (K93R), V2 (E14D/V92L) and V3 (K93R/N122K), through molecular and phenotypic approaches. We demonstrated that cells containing V1 achieved higher colony formation and showed greater cell migration ability when compared to other variants, but no difference in cell immortalization ability was observed. At the molecular level, the three variants formed complexes with E6-associated protein (E6AP) and p53 as efficiently as the prototype. They degraded p53 and PSD95/Dlg/ZO-1(PDZ) proteins, including MAGI-1c and Dlg, to a similar extent. They also exhibited a similar subcellular localization, and shared a half-life of approximately 45 min. Our findings provide a clearer picture of HPV-52 E6 variant oncogenicity, which is important for further studies aiming to understand the unusually high prevalence of HPV-52 among cervical cancers in East Asia.

International audience; Various 3-amino-, 3-aryloxy- and alkoxy-6-arylpyridazines have been synthesized by an electrochemical reductive cross-coupling between 3-amino-, 3-aryloxy- or 3-alkoxy-6-chloropyridazines and aryl or heteroaryl halides. In vitro antiproliferative activity of these products was evaluated against a representative panel of cancer cell lines (HuH7, CaCo-2, MDA-MB-231, HCT116, PC3, NCI-H727, HaCaT) and oncogenicity prevention of the more efficient derivatives was highlighted on human breast cancer cell line MDA-MB 468-Luc prior establishing their interaction with p44/42 and Akt-dependent signaling pathways.

Human populations of Black African ancestry have a relatively high risk of aggressive cancer types, including keratinocyte‐derived squamous cell carcinomas (SCCs). We show that primary keratinocytes (HKCs) from Black African (Black) versus White Caucasian (White) individuals have on average higher oncogenic and self‐renewal potential, which are inversely related to mitochondrial electron transfer chain activity and ATP and ROS production. HSD17B7 is the top‐ranked differentially expressed gene in HKCs and Head/Neck SCCs from individuals of Black African versus Caucasian ancestries, with several ancestry‐specific eQTLs linked to its expression. Mirroring the differences between Black and White HKCs, modulation of the gene, coding for an enzyme involved in sex steroid and cholesterol biosynthesis, determines HKC and SCC cell proliferation and oncogenicity as well as mitochondrial OXPHOS activity. Overall, the findings point to a targetable determinant of cancer susceptibility among different human populations, amenable to prevention and management of the disease., Differences in individuals' cancer susceptibility can be attributed, in part, to specific genetic and epigenetic variations. Human populations of Black African ancestry have a higher risk of aggressive cancer of various types, including keratinocyte‐derived squamous cell carcinomas (SCCs).

CRISPR/Cas technology has revolutionized the fields of the genome- and epigenome-editing by supplying unparalleled control over genomic sequences and expression. Lentiviral vector (LV) systems are one of the main delivery vehicles for the CRISPR/Cas systems due to (i) its ability to carry bulky and complex transgenes and (ii) sustain robust and long-term expression in a broad range of dividing and non-dividing cells in vitro and in vivo. It is thus reasonable that substantial effort has been allocated towards the development of the improved and optimized LV systems for effective and accurate gene-to-cell transfer of CRISPR/Cas tools. The main effort on that end has been put towards the improvement and optimization of the vector’s expression, development of integrase-deficient lentiviral vector (IDLV), aiming to minimize the risk of oncogenicity, toxicity, and pathogenicity, and enhancing manufacturing protocols for clinical applications required large-scale production. In this review, we will devote attention to (i) the basic biology of lentiviruses, and (ii) recent advances in the development of safer and more efficient CRISPR/Cas vector systems towards their use in preclinical and clinical applications. In addition, we will discuss in detail the recent progress in the repurposing of CRISPR/Cas systems related to base-editing and prime-editing applications.

Persistent infections of high-risk human papillomaviruses (HPVs) are the leading cause of cervical cancers. We collected cervical exfoliated cell samples from females in Changsha city, Hunan Province and obtained 358 viral genomes of four major HPV types, including HPV 16 (n=82), 18 (n=35), 52 (n=121) and 58 (n=100). The lineage/sublineage distribution of the four HPVs confirmed previous epidemiological reports, with the predominant prevailing sublineage as A4 (50%), A1 (37%) and A3 (13%) for HPV16, A1 (83%) for HPV18, B2 (86%) for HPV52 and A1 (65%), A3 (19%) and A2 (12%) for HPV58. We also identified two potentially novel HPV18 sublineages, i.e. A6 and A7. Virus mutation analysis further revealed the presence of HPV16 and HPV58 strains associated with potentially high oncogenicity. These findings expanded our knowledge on the HPV genetic diversity in China, providing valuable evidence to facilitate HPV DNA screening, vaccine effectiveness evaluation and control strategy development.

Liu H, Zhang X, Jin X, et al. Cancer Manag Res. 2020;12:9915–9928. The Editor and Publisher of Cancer Management and Research wish to publish an Expression of Concern for the published article. Following publication, concerns were raised about the scientific integrity of the articles content. We reached out to the authors requesting they supply information that would confirm the integrity of the data. The authors provided several files in response to our queries but they did not satisfy our requirements to confirm the authenticity of some types of data. In addition, there were unexplained similarities between some of the figures presented in this article, and figures presented in articles by different authors groups. As yet, the authors have not provided a satisfactory explanation for this. Therefore, as we continue to work through the issues raised, we advise readers to interpret the information presented in the article with due caution. The authors have been notified about this Expression of Concern. Read the original article

Over the last decade, the generation and differentiation of induced pluripotent stem cells (iPSCs) from somatic cells highlights one of the most groundbreaking discoveries in science and medicine. iPSCs has become an indispensable tool for elucidating a pathology of different diseases, drug screening, and development. A critical step for advancing iPSC technology is the establishment of delivery systems for introducing reprogramming factors into embryonic and somatic cells. Retroviral and lentiviral vectors are among the most common delivery vehicles used to induce iPSCs generation and differentiation, due to their ability to stably transduce a broad range of postmitotic cells and mediate high levels of gene expression. Nevertheless, integration capacity of the vectors increases a risk of insertional mutagenicity and oncogenicity and thus raises serious safety concerns regarding their use in clinical studies. Furthermore, residual transgene expression in virus‐carrying human iPSCs can alter the differentiation potential of the cells and profoundly affect their molecular characteristics. Integrase-deficient viruses including adenoviruses (Ad), Sendai virus–based vectors (SeVs), and integrase-deficient lentiviral vectors (IDLVs) provide valuable alternative to the integrase-competent counterparts, and as such are under intensive development and exploration. In this chapter (i) we provide a systemic overview of retroviral and lentiviral vectors employed for the generation and differentiation of iPSCs; (ii) we discuss construction of the vectors harboring reprogramming factor combinations; (iii) we outline in detail pros and cons of integrating viruses for iPSC generation; (iv) we will highlight the progress made in the field of nonintegrating vectors developed for the iPSCs production and differentiation.

BackgroundSystematic perturbation screens provide comprehensive resources for the elucidation of cancer driver genes, including rarely mutated genes that are missed by approaches focused on frequently mutated genes and driver genes for which the basis for oncogenicity is non-genetic. The perturbation of many genes in relatively few cell lines in such functional screens necessitates the development of specialized computational tools with sufficient statistical power.ResultsHere we developed APSiC (Analysis ofPerturbationScreens foridentifying novelCancer genes) that can identify genetic and non-genetic drivers even with a limited number of samples. Applying APSiC to the large-scale deep shRNA screen Project DRIVE, APSiC identified well-known, pan-cancer genetic drivers, novel putative genetic drivers known to be dysregulated in specific cancer types and the context dependency of mRNA-splicing between cancer types. Additionally, APSiC discovered a median of 28 and 35 putative non-genetic oncogenes and tumor suppressor genes, respectively, for individual cancer types, including genes involved in genome stability maintenance and cell cycle. We functionally demonstrated thatLRRC4B, a putative non-genetic tumor suppressor gene that has not previously been associated with carcinogenesis, suppresses proliferation by delaying cell cycle and modulates apoptosis in breast cancer.ConclusionWe demonstrate APSiC is a robust statistical framework for discovery of novel cancer genes through analysis of large-scale perturbation screens. The analysis of DRIVE using APSiC is provided as a web portal and represents a valuable resource for the discovery of novel cancer genes.

It has long been established that group A human adenoviruses (HAdV-A12, -A18, and -A31) can cause tumors in newborn rodents, with tumorigenicity related to the presence of a unique spacer region located between conserved regions 2 and 3 within the HAdV-A12 early region 1A (E1A) protein. Group B adenoviruses are weakly oncogenic, whereas most of the remaining human adenoviruses are nononcogenic. In an attempt to understand better the relationship between the structure of the AdE1A spacer region and oncogenicity of HAdVs, the structures of synthetic peptides identical or very similar to the adenovirus 12 E1A spacer region were determined and found to be α-helical using nuclear magnetic resonance (NMR) spectroscopy. This contrasts significantly with some previous suggestions that this region is unstructured. Using available predictive algorithms, the structures of spacer regions from other E1As were also examined, and the extent of the predicted α-helix was found to correlate reasonably well with the tumorigenicity of the respective virus. We suggest that this may represent an as-yet-unknown binding site for a partner protein required for tumorigenesis. IMPORTANCE This research analyzed small peptides equivalent to a region within the human adenovirus early region 1A protein that confers, in part, tumor-inducing properties to various degrees on several viral strains in rats and mice. The oncogenic spacer region is α-helical, which contrasts with previous suggestions that this region is unstructured. The helix is characterized by a stretch of amino acids rich in alanine residues that are organized into a hydrophobic, or “water-hating,” surface that is considered to form a major site of interaction with cellular protein targets that mediate tumor formation. The extent of α-helix in E1A from other adenovirus species can be correlated to a limited degree to the tumorigenicity of that virus. Some serotypes show significant differences in predicted structural propensity, suggesting that the amino acid type and physicochemical properties are also of importance.

The p53 protein is mutated in about 50% of human cancers. Aside from losing its tumor-suppressive activities, mutant p53 may acquire pro-oncogenic activity, which is facilitated by two underlying mechanisms. The first mechanism is the inhibition of co-expressed wild-type p53 (WTp53) activity, dubbed the dominant-negative effect (DNE). The second mechanism is a neomorphic pro-oncogenic activity that does not involve the inhibition of WTp53, termed gain-of-function (GOF). Throughout the years, both mechanisms were demonstrated in a plethora of in vitro and in vivo models. However, whether both account for protumorigenic activities of mutant p53 and in which contexts is still a matter of ongoing debate. Here, we discuss evidence for both DNE and GOF in a variety of models. These models suggest that both GOF and DNE can be relevant, but are highly dependent on the specific mutation type, genetic and cellular context and even the phenotype that is being assessed. In addition, we discuss how mutant and WTp53 might not exist as two separate entities, but rather as a continuum that may involve a balance between the two forms in the same cells, which could be tilted by various factors and drugs. Further elucidation of the factors that dictate the balance between the WT and mutant p53 states, as well as the factors that govern the impact of DNE and GOF in different cancer types, may lead to the development of more effective treatment regimens for cancer patients.

Cell culture based live attenuated influenza vaccines (LAIV) as an alternative to egg-based LAIV have been explored because of lack of easy access to SPF eggs for large scale production. In this study, feasibility of MDCK platform was assessed by including multiple LAIV strains covering both type A (H1 and H3) and type B seasonal strains as well as the candidate pandemic potential strains like A/H5 and A/H7 for the growth in MDCK cells. A risk assessment study was conducted on the cell banks to evaluate safety concerns related to tumorigenicity with a regulatory perspective. Tumorigenic potential of the MDCK cells was evaluated in nude mice (107cells/mouse) model system. The 50% tumor producing dose (TPD50) of MDCK cells was studied in SCID mice to determine the amount of cells required for induction of tumors. Further, we conducted an oncogenicity study in three sensitive rodent species as per the requirements specified in the WHO guidelines. We determined TPD50 value of 1.9 X 104 cells/mice through subcutaneous route. Our results suggest that, the intranasal route of administration of the cell culture based LAIV pose minimal to no risk of tumorigenicity associated with the host cells. Also, non-oncogenic nature of MDCK cells was demonstrated. Host cell DNA in the vaccine formulations was The present study clearly establishes the suitability of MDCK cells as a substrate for the manufacture of a safe and viable LAIV.

A subset of Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared to Palmostatin M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MEK inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes in modulating the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers.

Increasing evidence has suggested the crucial role cyclin-dependent kinases (CDKs) in the biology of hepatocellular carcinoma (HCC), a lethal malignancy with high morbidity and mortality. Hence, this study explored the modulatory effect of the putative cyclin-dependent kinase 11B (CDK11B)-mediated ubiquitination on HCC stem cells. The expression of CDK11B, SAM pointed domain-containing ETS transcription factor (SPDEF) and DOT1-like histone lysine methyltransferase (DOT1L) was determined by RT-qPCR and western blot analysis in HCC tissues and cells. The interaction among CDK11B, SPDEF, miR-448, and DOT1L was analyzed by Co-IP, ubiquitination-IP and ChIP assays, whereas their effects on the biological characteristics of HCC stem cells were assessed by sphere formation and colony formation assays. An in vivo xenograft tumor model was developed for validating the regulation of CDK11B in oncogenicity of HCC stem cells. We characterized the aberrant upregulation of CDK11B and downregulation SPDEF in HCC tissues and cells. CDK11B degraded SPDEF through ubiquitin-proteasome pathway, whereas SPDEF could bind to the miR-448 promoter and inhibit the expression of DOT1L by activating miR-448, whereby promoting self-renewal of HCC stem cells. Knockdown of CDK11B attenuated the self-renewal capability of HCC stem cells and their oncogenicity in vivo. These findings highlighted that blocking the CDK11B-induced degradation of SPDEF and enhancing miR-448-dependent inhibition of DOT1L may delay the progression of HCC by restraining self-renewal capability of HCC stem cells, representing novel targets for HCC management.

High mobility group AT-hook 2 (HMGA2) has been associated with increased cell proliferation and cell cycle dysregulation, leading to the ontogeny of varied tumor types and their metastatic potentials, a frequently used index of disease prognosis. In this review, we deepen our understanding of HMGA2 pathogenicity by exploring the mechanisms by which HMGA2 misexpression and ectopic expression induces mesenchymal and epithelial tumorigenesis respectively and distinguish the pathogenesis of benign from malignant mesenchymal tumors. Importantly, we highlight the regulatory role of let-7 microRNA family of tumor suppressors in determining HMGA2 misexpression events leading to tumor pathogenesis and focused on possible mechanisms by which HMGA2 could propagate lymphangioleiomyomatosis (LAM), benign mesenchymal tumors of the lungs. Lastly, we discuss potential therapeutic strategies for epithelial and mesenchymal tumorigenesis based on targeting the HMGA2 signaling pathway.

MOB1 deficiency promotes rapid onset and progression of oral SCC (OSCC) via YAP1 activation., Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common group of cancers in the world, and patients have a poor prognosis. Here, we present data indicating that YAP1 may be a strong driver of the onset and progression of oral SCC (OSCC), a major subtype of HNSCC. Mice with tongue-specific deletion of Mob1a/b and thus endogenous YAP1 hyperactivation underwent surprisingly rapid and highly reproducible tumorigenesis, developing tongue carcinoma in situ within 2 weeks and invasive SCC within 4 weeks. In humans, precancerous tongue dysplasia displays YAP1 activation correlating with reduced patient survival. Combinations of molecules mutated in OSCC may increase and sustain YAP1 activation to the point of oncogenicity. Strikingly, siRNA or pharmacological inhibition of YAP1 blocks murine OSCC onset in vitro and in vivo. Our work justifies targeting YAP1 as therapy for OSCC and perhaps HNSCC, and our mouse model represents a powerful tool for evaluating these agents.

Many drugs are developed for commonly occurring, well studied cancer drivers such as vemurafenib for BRAF V600E and erlotinib for EGFR exon 19 mutations. However, most tumors also harbor mutations which have an uncertain role in disease formation, commonly called Variants of Uncertain Significance (VUS), which are not studied or characterized and could play a significant role in drug resistance and relapse. Therefore, the determination of the functional significance of VUS and their response to Molecularly Targeted Agents (MTA) is essential for developing new drugs and predicting response of patients. Here we present a multi-scale deep convolutional neural network (DCNN) architecture combined with an in-vitro functional assay to investigate the functional role of VUS and their response to MTA’s. Our method achieved high accuracy and precision on a hold-out set of examples (0.98 mean AUC for all tested genes) and was used to predict the oncogenicity of 195 VUS in 6 genes. 63 (32%) of the assayed VUS’s were classified as pathway activating, many of them to a similar extent as known driver mutations. Finally, we show that responses of various mutations to FDA approved MTAs are accurately predicted by our platform in a dose dependent manner. Taken together this novel system can uncover the treatable mutational landscape of a drug and be a useful tool in drug development.

The p38 MAPK pathway is well known for its role in transducing stress signals from the environment. Many key players and regulatory mechanisms of this signaling cascade have been described to some extent. Nevertheless, p38 participates in a broad range of cellular activities, for many of which detailed molecular pictures are still lacking. Originally described as a tumor-suppressor kinase for its inhibitory role in RAS-dependent transformation, p38 can also function as a tumor promoter, as demonstrated by extensive experimental data. This finding has prompted the development of specific inhibitors that have been used in clinical trials to treat several human malignancies, although without much success to date. However, elucidating critical aspects of p38 biology, such as isoform-specific functions or its apparent dual nature during tumorigenesis, might open up new possibilities for therapy with unexpected potential. In this review, we provide an extensive description of the main biological functions of p38 and focus on recent studies that have addressed its role in cancer. Furthermore, we provide an updated overview of therapeutic strategies targeting p38 in cancer and promising alternatives currently being explored. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2017-85152-P and FEDER to E.d.N and PGC2018-094136-B-I00 and FEDER to F.P.], the AECC Foundation [PROYE18010POSA to F.P.) and the Catalan Government (2017 SGR 799 to E.d.N and F.P.). F.P. is a recipient of an ICREA Acadèmia award (Catalan Government). We gratefully acknowledge institutional funding from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) through the Centres of Excellence Severo Ochoa award, from the CERCA Programme of the Catalan Government, and from “Unidad de Excelencia María de Maeztu,” funded by the AEI (CEX2018-000792-M).

Epidemiological studies have revealed that a wild-type variant of HPV58 carrying an E7 variation, T20I/G63S (V1), is associated with a higher risk of cervical cancer. We previously reported that this increased oncogenicity could be the result of the virus’s greater ability to degrade pRB, thereby leading to an increased ability to grow in an anchorage-independent manner. In addition to this, this report further showed that this HPV variant induced activation of the AKT and K-Ras/ERK signaling pathways, thereby explaining its genuine oncogenicity in promoting cell proliferation, migration, invasion, and formation of tumors, all to a greater extent than the prototype HPV58 and other common variants., Human papillomavirus (HPV) type 58 is the third most commonly detected HPV type in cervical cancer among Eastern Asians. Our previous international epidemiological studies revealed that HPV58 carrying an E7 natural variant, T20I/G63S (designated V1), was associated with a higher risk of cervical cancer. We recently showed that V1 possesses a greater ability to immortalize and transform primary cells, as well as degrading pRB more effectively, than the prototype and other common variants. In this study, we performed a series of phenotypic and molecular assays using physiologically relevant in vitro and in vivo models to compare the oncogenicity of V1 with that of the prototype and other common natural variants. Through activation of the AKT and K-Ras/extracellular signal-regulated kinase (ERK) signaling pathways, V1 consistently showed greater oncogenicity than the prototype and other variants, as demonstrated by increased cell proliferation, migration, and invasion, as well as induction of larger tumors in athymic nude mice. This study complements our previous epidemiological and molecular observations pinpointing the higher oncogenicity of V1 than that of the prototype and all other common variants. Since V1 is more commonly found in eastern Asia, our report provides insight into the design of HPV screening assays and selection of components for HPV vaccines in this region. IMPORTANCE Epidemiological studies have revealed that a wild-type variant of HPV58 carrying an E7 variation, T20I/G63S (V1), is associated with a higher risk of cervical cancer. We previously reported that this increased oncogenicity could be the result of the virus’s greater ability to degrade pRB, thereby leading to an increased ability to grow in an anchorage-independent manner. In addition to this, this report further showed that this HPV variant induced activation of the AKT and K-Ras/ERK signaling pathways, thereby explaining its genuine oncogenicity in promoting cell proliferation, migration, invasion, and formation of tumors, all to a greater extent than the prototype HPV58 and other common variants.

Neural stem cells (NSCs) persist in the adult mammalian brain in two neurogenic regions: the subventricular zone lining the lateral ventricles and the dentate gyrus of the hippocampus. Compelling evidence suggests that NSCs of the subventricular zone could be the cell type of origin of glioblastoma, the most devastating brain tumor. Studies in glioblastoma patients revealed that NSCs of the tumor-free subventricular zone, harbor cancer-driver mutations that were found in the tumor cells but were not present in normal cortical tissue. Endogenous mutagenesis can also take place in hippocampal NSCs. However, to date, no conclusive studies have linked hippocampal mutations with glioblastoma development. In addition, glioblastoma cells often invade or are closely located to the subventricular zone, whereas they do not tend to infiltrate into the hippocampus. In this review we will analyze possible causes by which subventricular zone NSCs might be more susceptible to malignant transformation than their hippocampal counterparts. Cellular and molecular differences between the two neurogenic niches, as well as genotypic and phenotypic characteristics of their respective NSCs will be discussed regarding why the cell type originating glioblastoma brain tumors has been linked mainly to subventricular zone, but not to hippocampal NSCs. Universidad de Sevilla 2020/0000081

Helicobacter pylori (H. pylori) is one of the most extensively studied Gram-negative bacteria due to its implication in gastric cancer. The oncogenicity of H. pylori is associated with cytotoxin-associated gene A (CagA), which is injected into epithelial cells lining the stomach. Both the C- and N-termini of CagA are involved in the interaction with several host proteins, thereby disrupting vital cellular functions, such as cell adhesion, cell cycle, intracellular signal transduction, and cytoskeletal structure. The N-terminus of CagA interacts with the tumor-suppressing protein, apoptosis-stimulating protein of p53 (ASPP2), subsequently disrupting the apoptotic function of tumor suppressor gene p53. Here, we present the in-depth molecular dynamic mechanism of the CagA–ASPP2 interaction and highlight hot-spot residues through in silico mutagenesis. Our findings are in agreement with previous studies and further suggest other residues that are crucial for the CagA–ASPP2 interaction. Furthermore, the ASPP2-binding pocket possesses potential druggability and could be engaged by decoy peptides, identified through a machine-learning system and suggested in this study. The binding affinities of these peptides with CagA were monitored through extensive computational procedures and reported herein. While CagA is crucial for the oncogenicity of H. pylori, our designed peptides possess the potential to inhibit CagA and restore the tumor suppressor function of ASPP2.

Oral squamous cell carcinoma (OSCC) is a common malignancy worldwide. This study clarified the oncogenic role of miR-134 in OSCC. Reporter assays, using both wild-type and mutant constructs, confirmed that Programmed Cell Death 7 (PDCD7) gene was a potential target of miR-134. The OSCC cells exogenously expressed miR-134 exhibited reduced PDCD7 expression. As expected, exogenous miRZip-134 expression increased PDCD7 expression in the OSCC cells; additionally, PDCD7 expression suppressed the oncogenicity of the OSCC cells. By contrast, PDCD7 knockout through gene editing increased in vitro oncogenicity and neck nodal metastasis in mice, and reduced E-cadherin (E-cad) expression. PDCD7 transactivated E-cad expression via the GC-box in the promoter. Moreover, miR-134-associated cellular transformation and E-cad downregulation was attenuated by PDCD7. Downregulation of both PDCD7 and E-cad and high levels miR-134 expression was observed in OSCC tumor tissues. Activation of the miR-134-PDCD7-E-cad pathogenesis cascade occurred early during the human and murine oral carcinogenesis process. In conclusion, the oncogenic effect of miR-134 in oral carcinoma is mediated by reducing PDCD7 and E-cad expression.

The focus of precision cancer medicine is the use of patient genetic signatures to predict disease occurrence and course and tailor approaches to individualized treatment to improve patient outcomes. The rearranged during transfection (RET) receptor tyrosine kinase represents a paradigm for the power of personalized cancer management to change cancer impact and improve quality of life. Oncogenic activation of RET occurs through several mechanisms including activating mutations and increased or aberrant expression. Activating RET mutations found in the inherited cancer syndrome multiple endocrine neoplasia 2 permit early diagnosis, predict disease course and guide disease management to optimize patient survival. Rearrangements of RET found in thyroid and lung tumors provide insights on potential disease aggressiveness and offer opportunities for RET-targeted therapy. Aberrant RET expression in a subset of cases is associated with tumor dissemination, resistance to therapies and/or poorer prognosis in multiple cancers. The potential of RET targeting through repurposing of small-molecule multikinase inhibitors, selective RET inhibitors or other novel approaches provides exciting opportunities to individualize therapies across multiple pathologies where RET oncogenicity contributes to cancer outcomes.

Papillomaviruses (PVs) are complex viruses which infect the skin or mucosae of a broad range of amniotes worldwide. They cause benign or malignant lesions depending on environmental factors, virus oncogenicity and the location of infection. Bovine papillomaviruses (BPVs) are the second most studied PVs beyond human PVs. In the past few years, genetic characterization of animal PVs has increased due to the availability of new techniques, which simplified the sequencing of entire genomes. Therefore, this review aims to provide an update of the current epidemiology, classification and genome features of ruminant PVs (mainly BPVs) affecting animals worldwide. The review also aimed to clarify the key differences between the high-risk Delta papillomaviruses and the seemingly low-risk Xi, Epsilon, Dyoxi and Dyokappapillomavirus as well as the recently described PVs BPV18, 19, 21 and PpuPV1 that belongs to an unclassified genus.

Highlights • High level of TFRC promotes the glioma development. • Hsa-miR-144-3p inhibitor glioma growth by targeting TFRC. • LncRNA RP1-86C11.7 exacerbates glioma progression through sponging to hsa-miR-144-3p, resulting in TFRC upregulation., Glioblastoma (GBM) remains the most common and malignant tumor of the human central nervous system. Increasing evidence has highlighted that tumor cells with high transferrin receptor (TFRC) expression show advantages in growth. Long noncoding RNAs (lncRNAs) are related to glioma progression by mediating microRNAs (miRNAs). However, the underlying mechanism among TFRC, miRNA and lncRNA in GBM is limited. In the current study, we identified a new lncRNA-induced signaling mechanism that regulates the TFRC levels in GBM. The TFRC level was higher in glioma cell lines, and elevated TFRC expression promoted the proliferation and survival of glioma cells. Further study showed that hsa-miR-144a-3p bound to the 3′-UTR of TFRC mRNA and inhibited its expression, preventing the malignant properties of glioma cells, such as proliferation and survival. We also found that the lncRNA RP1-86C11.7 sponges hsa-miR-144-3p to suppress its protective role in glioma. RP1-86C11.7 overexpression in glioma cells elevated TFRC expression, increased the intracellular free iron level, and deteriorated oncogenicity, with a significant reduction in hsa-miR-144-3p. By contrast, silencing RP1-86C11.7 upregulated the hsa-miR-144-3p level, resulting in decreased TFRC expression and repressed glioma progression. However, the effect of silencing RP1-86C11.7 was reversed with simultaneous hsa-miR-144-3p inhibitor treatment: the TFRC level, intracellular iron level and proliferation in glioma cells increased. Mechanistically, our data indicated that RP1-86C11.7 exacerbates the malignant behavior of glioma through the hsa-miR-144-3p/TFRC axis. RP1-86C11.7 may be a potential biomarker or target to treat glioma in the future.

Viruses may affect human health by altering host immunity and the genome, contributing to chronic disease and cancer. The purpose of this study was to examine evidence of oncogenicity accompanying integrations of non-hepatitis viruses into the liver cancer genome through analysis of a cohort of 147 Thai liver cancer patients comprised of 47 hepatocellular carcinoma (HCC) cases and 100 intrahepatic cholangiocarcinoma (iCCA) cases. For each case, we generated paired RNASeq data from cancerous tissue and adjacent non-cancerous tissue. Initial analysis with PathSeq comparing viruses with RefSeq genomes revealed that only Adeno-associated viruses (AAV) were differentially and predominantly present in the non-cancer samples (p < 9.4e-6, two-sided Fisher test). However, J. Zucman-Rossi and colleagues (Nault et al., Nat. Genet. 2015; 47:1187-1193) reported that integrations of AAV resembling the strains AAV2 or AAV13 near human genes such as CCNA2, CCNE1 are oncogenic. Understanding when AAV integration is oncogenic is important because AAV2-derived vectors are used in gene therapy. To investigate the apparent discrepancy, we performed AAV-targeted viral capture DNA sequencing of the cancerous tissue and adjacent non-cancerous tissue from each patient with AAV. One patient has an integration of AAV2/13 into CCNA2, expanded in the non-cancer sample and further expanded in the cancer sample that has 10,006 chimeric AAV/CCNA2 DNA reads. We validated that this integration substantially increased mRNA expression of CCNA2, replicating the previous findings. In contrast, we found ten patients with AAV integrations into other loci only in the non-cancer samples and two other patients with AAV integrations into other loci only in the cancer samples. These single-sample AAV integrations did not significantly increase the expression of the target gene, if any, suggesting that they are not oncogenic. All previously reported AAV integrations have been demonstrated only in HCC. Similarly, in our analysis, the only oncogenic integration was in a patient with HCC. Among the ten non-oncogenic integrations in non-cancer samples, one is HCC and nine are iCCA. Both non-oncogenic integrations in cancer samples were in iCCA. Analysis of all previously published AAV integrations and the new AAV integrations we identified showed that almost all the integrations reported as oncogenic overlap the poorly characterized X gene, while the non-oncogenic integrations need not overlap the X gene. This finding explains why the oncogenic AAV integrations are necessarily from AAV2 or a similar strain since other sequenced AAV strains do not contain the X gene. This would suggest re-engineering AAV vectors to make the X gene non-functional, to retain the useful properties of these vectors and concomitantly mitigate the risk of liver cancer in AAV-therapy recipients. Citation Format: Alejandro A. Schaffer, Dana Dominguez, E. M. Gertz, Lesley M. Chapman, Anuradha Budhu, Marshonna Forgues, Jittiporn Chaisaingmongkol, Siritida Rabibhadana, Benjarath Pupacdi, Xiaolin Wu, Curtis C. Harris, Mathuros Ruchirawat, Eytan Ruppin, Xin W. Wang. Oncogenicity of adeno-associated virus (AAV) integration into the genomes of liver cancer patients depends on the overlap between the AAV integration site and the AAV X gene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2658.