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ELife Sep 2023Identification oncogenes is fundamental to revealing the molecular basis of cancer. Here, we found that is overexpressed in human prostate cancer cells and prostate...
Identification oncogenes is fundamental to revealing the molecular basis of cancer. Here, we found that is overexpressed in human prostate cancer cells and prostate tumors, but its expression is absent in normal prostate epithelial cells and low in benign prostatic hyperplasia. is a FOX transcription factor family member and tightly associated with vocal development. To date, little is known regarding the link of to prostate cancer. We observed that high expression and frequent amplification are significantly associated with high Gleason score. Ectopic expression of induces malignant transformation of mouse NIH3T3 fibroblasts and human prostate epithelial cell RWPE-1. Conversely, knockdown suppresses the proliferation of prostate cancer cells. Transgenic overexpression of in the mouse prostate causes prostatic intraepithelial neoplasia. Overexpression of aberrantly activates oncogenic MET signaling and inhibition of MET signaling effectively reverts the -induced oncogenic phenotype. CUT&Tag assay identified FOXP2-binding sites located in and its associated gene . Additionally, the novel recurrent fusion identified in prostate tumors results in high expression of truncated FOXP2, which exhibit a similar capacity for malignant transformation. Together, our data indicate that is involved in tumorigenicity of prostate.
Topics: Animals; Humans; Male; Mice; Animals, Genetically Modified; Forkhead Transcription Factors; NIH 3T3 Cells; Oncogenes; Prostate; Prostatic Neoplasms
PubMed: 37668356
DOI: 10.7554/eLife.81258 -
International Journal of Oncology Nov 2023Salt inducible kinases (SIKs) with three subtypes SIK1, SIK2 and SIK3, belong to the AMP‑activated protein kinase family. They are expressed ubiquitously in humans.... (Review)
Review
Salt inducible kinases (SIKs) with three subtypes SIK1, SIK2 and SIK3, belong to the AMP‑activated protein kinase family. They are expressed ubiquitously in humans. Under normal circumstances, SIK1 regulates adrenocortical function in response to high salt or adrenocorticotropic hormone stimulation, SIK2 is involved in cell metabolism, controlling insulin signaling and gluconeogenesis and SIK3 coordinates with the mTOR complex, promoting cancer. The dysregulation of SIKs has been widely detected in various types of cancers. Based on most of the existing studies, SIK1 is mostly considered a tumor inhibitor, SIK2 and SIK3 are usually associated with tumor promotion. However, the functions of SIKs have shown contradictory in certain tumors, suggesting that SIKs cannot be simply classified as oncogenes or tumor suppressor genes. The present review provided a comprehensive summary of the roles of SIKs in the initiation and progression of different cancers, aiming to elucidate their clinical value and discuss potential strategies for targeting SIKs in cancer therapy.
Topics: Humans; Oncogenes; Neoplasms; AMP-Activated Protein Kinases; Cell Transformation, Neoplastic
PubMed: 37654200
DOI: 10.3892/ijo.2023.5566 -
Biochimica Et Biophysica Acta. Reviews... Sep 2023Oncogenic signaling involved in tumor metabolic reprogramming. Tumorigenesis was not only determined by the mutations or deletion of oncogenes but also accompanied by... (Review)
Review
Oncogenic signaling involved in tumor metabolic reprogramming. Tumorigenesis was not only determined by the mutations or deletion of oncogenes but also accompanied by the reprogramming of cellular metabolism. Metabolic alterations play a crucial regulatory role in the development and progression of tumors. Oncogenic PI3K/AKT signaling mediates the metabolic switch in cancer cells and immune cells in the tumor microenvironment. PI3K/AKT and its downstream effector branch off and connect to multiple steps of metabolism, such as glucose, lipids, and amino acids. Thus, PI3K inhibitor could effectively regulate metabolic pathway and impede the oncogenic process and some key metabolic proteins or critical enzymes also constitute biomarkers for tumor diagnosis and treatment. In the current review, we summarize the significant effect of PI3K/AKT signaling toward tumor metabolism, it enables us to obtain the better understanding for this interaction and develop more effective therapeutic strategies targeting cancer cell metabolism.
Topics: Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Neoplasms; Oncogenes; Tumor Microenvironment
PubMed: 37499988
DOI: 10.1016/j.bbcan.2023.188952 -
Nature Communications Oct 2023Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between...
Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged-the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context-and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.
Topics: Mice; Humans; Animals; Proto-Oncogene Proteins p21(ras); Oncogenes; Lung Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Mutation
PubMed: 37828026
DOI: 10.1038/s41467-023-42156-y -
Nature Communications May 2024Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that...
Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms. Short-read sequencing identifies ERBB2, MYC, MDM2, and HMGA2 as the most frequent oncogenes amplified in extrachromosomal DNAs. We resolve complex extrachromosomal DNA and breakage-fusion-bridge cycles amplicons by integrating of de-novo assemblies and DNA methylation in nine long-read sequenced cases. Complex amplicons shared between precancerous biopsy and late-stage tumor, an enrichment of putative enhancer elements and mobile element insertions are potential drivers of complex amplicons' origin. We find that patient-derived organoids recapitulate extrachromosomal DNA observed in the primary tumors and single-cell DNA sequencing capture extrachromosomal DNA-driven clonal dynamics across passages. Prospectively, long-read and single-cell DNA sequencing technologies can lead to better prediction of clonal evolution in esophageal adenocarcinoma.
Topics: Humans; Esophageal Neoplasms; Adenocarcinoma; Organoids; Gene Amplification; DNA Methylation; Oncogenes; Male; Sequence Analysis, DNA; Clonal Evolution; Female
PubMed: 38744814
DOI: 10.1038/s41467-024-47619-4 -
The Journal of Clinical Investigation Oct 2023Carcinogen exposure has been associated with enhanced cancer immunogenicity that is often attributed to neoantigen generation. However, the broader,...
Carcinogen exposure has been associated with enhanced cancer immunogenicity that is often attributed to neoantigen generation. However, the broader, neoantigen-independent impact of carcinogens on immune responses to cancer cells remains underexplored. In this issue of the JCI, Huang et al. uncover a mechanism wherein carcinogen-treated cancer cells exhibit an inability to establish an immunosuppressive tumor microenvironment (TME) due to reduced M-CSF expression. Intriguingly, the so-called carcinogen-induced tumor-associated macrophages (TAMs) within this TME exhibited anti-tumor properties instead of the conventional immunosuppressive phenotype. This phenomenon extended to human lung cancers, as evidenced by TAM reprogramming in smokers versus nonsmokers. This study substantially advances our understanding of carcinogen-mediated effects on cancer immunogenicity, potentially redirecting approaches to cancer immunotherapy.
Topics: Humans; Carcinogens; Immunotherapy; Immunosuppressive Agents; Lung Neoplasms; Phenotype; Tumor Microenvironment; Neoplasms
PubMed: 37843275
DOI: 10.1172/JCI174319 -
Scientific Reports Sep 2023E-cigarettes are now very popular in the world. Compared to traditional cigarettes, e-cigarettes are often considered safer and healthier. However, their safety remains...
E-cigarettes are now very popular in the world. Compared to traditional cigarettes, e-cigarettes are often considered safer and healthier. However, their safety remains controversial and requires further research and regulation. In this study, we aimed to understand the possible hazards to humans of four compounds (formaldehyde, acetaldehyde, acrolein, and acetone) and seven heavy metals (arsenic, cadmium, manganese, lead, copper, nickel, and chromium) contained in e-cigarette liquids and aerosols and perform a health risk assessment. We searched PubMed, CNKI, and other databases for relevant literature to obtain data on organic compounds and heavy metals in e-cigarette liquids and aerosols, and conducted acute, chronic, and carcinogenic risk assessments of various chemicals by different exposure routes. This study showed that exposure to four organic compounds and seven heavy metals in e-cigarette aerosols and e-liquids can cause varying levels of health risks in humans through different routes, with the inhalation route posing a higher overall risk than dermal exposure and oral intake. Various chemicals at high exposure doses can produce health risks beyond the acceptable range. E-cigarette designers must improve their products by changing the composition of the e-liquid and controlling the power of the device to reduce the health effects on humans.
Topics: Humans; Carcinogens; Electronic Nicotine Delivery Systems; Carcinogenesis; Metals, Heavy; Arsenic
PubMed: 37749131
DOI: 10.1038/s41598-023-43112-y -
Environmental Research Aug 2023Glyphosate is a broad-spectrum and one of the most widely used herbicides in the world, which has led to its high environmental dissemination. In 2015, the International... (Review)
Review
Glyphosate is a broad-spectrum and one of the most widely used herbicides in the world, which has led to its high environmental dissemination. In 2015, the International Agency for Research on Cancer stated that glyphosate was a probable human carcinogen. Since then, several studies have provided new data about the environmental exposure of glyphosate and its consequences on human health. Thus, the carcinogenic effects of glyphosate are still under debate. This work aimed to review glyphosate occurrence and exposure since 2015 up to date, considering studies associated with either environmental or occupational exposure and the epidemiological assessment of cancer risk in humans. These articles showed that herbicide residues were detectable in all spheres of the earth and studies on the population showed an increase in the concentration of glyphosate in biofluids, both in the general population and in the occupationally exposed population. However, the epidemiological studies under review provided limited evidence for the carcinogenicity of glyphosate, which was consistent with the International Agency for Research on Cancer classification as a probable carcinogen.
Topics: Humans; Environmental Exposure; Occupational Exposure; Carcinogens; Herbicides; Neoplasms; Glyphosate
PubMed: 37209985
DOI: 10.1016/j.envres.2023.116201 -
Wiley Interdisciplinary Reviews. RNA 2024Long noncoding RNAs (lncRNA) are a class of non-coding RNAs greater than 200 bp in length with limited peptide-coding function. The transcription of LINC00152 is... (Review)
Review
Long noncoding RNAs (lncRNA) are a class of non-coding RNAs greater than 200 bp in length with limited peptide-coding function. The transcription of LINC00152 is derived from chromosome 2p11.2. Many studies prove that LINC00152 influences the progression of various tumors via promoting the tumor cells malignant phenotype, chemoresistance, and immune escape. LINC00152 is regulated by multiple transcription factors and DNA hypomethylation. In addition, LINC00152 participates in the regulation of complex molecular signaling networks through epigenetic regulation, protein interactions, and competitive endogenous RNA (ceRNA). Here, we provide a systematic review of the upstream regulatory factors of LINC00152 expression level in different types of tumors. In addition, we revisit the main functions and mechanisms of LINC00152 as driver oncogene and biomarker in pan-cancer. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Methods > RNA Analyses in Cells RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes.
Topics: RNA, Long Noncoding; Humans; Neoplasms; Oncogenes; Gene Expression Regulation, Neoplastic
PubMed: 38702938
DOI: 10.1002/wrna.1851 -
Cell Death & Disease Sep 2023Oncogene Moesin plays critical role in initiation, progression, and metastasis of multiple cancers. It exerts oncogenic activity due to its high-level expression as well...
Oncogene Moesin plays critical role in initiation, progression, and metastasis of multiple cancers. It exerts oncogenic activity due to its high-level expression as well as posttranslational modification in cancer. However, factors responsible for its high-level expression remain elusive. In this study, we identified positive as well as negative regulators of Moesin. Our study reveals that Moesin is a cellular target of F-box protein FBXW2. We showed that FBXW2 suppresses breast cancer progression through directing proteasomal degradation of Moesin. In contrast, AKT kinase plays an important role in oncogenic function of Moesin by protecting it from FBXW2-mediated proteasomal degradation. Mechanistically, AKT phosphorylates Moesin at Thr-558 and thereby prevents its degradation by FBXW2 via weakening the association between FBXW2 and Moesin. Further, accumulated Moesin prevents FBXW2-mediated degradation of oncogene SKP2, showing that Moesin functions as an upstream regulator of oncogene SKP2. In turn, SKP2 stabilizes Moesin by directing its non-degradable form of polyubiquitination and therefore AKT-Moesin-SKP2 oncogenic axis plays crucial role in breast cancer progression. Collectively, our study reveals that FBXW2 functions as a tumor suppressor in breast cancer by restricting AKT-Moesin-SKP2 axis. Thus, AKT-Moesin-SKP2 axis may be explored for the development of therapeutics for cancer treatment.
Topics: Humans; Cell Transformation, Neoplastic; F-Box Proteins; Microfilament Proteins; Oncogenes; Proto-Oncogene Proteins c-akt; Breast Neoplasms
PubMed: 37736741
DOI: 10.1038/s41419-023-06127-x