Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (7)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: RAF1 (cancer-related)
Xia R, Sun L, Liao J, et al.Inhibition of Pancreatic Carcinoma Growth Through Enhancing ω-3 Epoxy Polyunsaturated Fatty Acid Profile by Inhibition of Soluble Epoxide Hydrolase.
Anticancer Res. 2019; 39(7):3651-3660 [PubMed
] Related Publications
BACKGROUND/AIM: Cytochrome P450 epoxygenase is a major enzyme involved in the metabolism of ω-3 polyunsaturated fatty acids (PUFAs) to produce biologically active ω-3 epoxy fatty acids (ω-3 epoxides). In general, all epoxy PUFAs including ω-3 epoxides are quickly metabolized/inactivated by soluble epoxide hydrolase (sEH) to form diol products. The aims of this study were to determine the effect and mechanism of fat-1 transgene, and ω-3 PUFA combined with sEH gene knockout or inhibitor on inhibiting pancreatic cancer and the related mechanisms involved.
MATERIALS AND METHODS: PK03-mutant Kras
RESULTS: Significant decreases of weight and size of the PK03 pancreatic carcinoma were observed in the fat-1 transgenic mice treated with sEH inhibitor compared to those of C57BL/6J control mice fed with AIN-76A diet (weight: 0.28±0.04 g vs. 0.58±0.06 g; size: 187.0±17.5 mm
CONCLUSION: ω-3 epoxy products from ω-3 PUFA metabolism play a crucial role in inhibiting pancreatic cancer growth, and use of ω-3 PUFAs combined with sEH inhibition is a strategy with high potential for pancreatic cancer treatment and prevention.
Many gene fusions are reported in tumours and for most their role remains unknown. As fusions are used for diagnostic and prognostic purposes, and are targets for treatment, it is crucial to assess their function in cancer. To systematically investigate the role of fusions in tumour cell fitness, we utilized RNA-sequencing data from 1011 human cancer cell lines to functionally link 8354 fusion events with genomic data, sensitivity to >350 anti-cancer drugs and CRISPR-Cas9 loss-of-fitness effects. Established clinically-relevant fusions were identified. Overall, detection of functional fusions was rare, including those involving cancer driver genes, suggesting that many fusions are dispensable for tumour fitness. Therapeutically actionable fusions involving RAF1, BRD4 and ROS1 were verified in new histologies. In addition, recurrent YAP1-MAML2 fusions were identified as activators of Hippo-pathway signaling in multiple cancer types. Our approach discriminates functional fusions, identifying new drivers of carcinogenesis and fusions that could have clinical implications.
Jin X, Li Y, Guo Y, et al.ERα is required for suppressing OCT4-induced proliferation of breast cancer cells via DNMT1/ISL1/ERK axis.
Cell Prolif. 2019; 52(4):e12612 [PubMed
] Related Publications
OBJECTIVE: POU5F1 (OCT4) is implicated in cancer stem cell self-renewal. Currently, some studies have shown that OCT4 has a dual function in suppressing or promoting cancer progression. However, the precise molecular mechanism of OCT4 in breast cancer progression remains unclear.
MATERIALS AND METHODS: RT-PCR and Western blot were utilized to investigate OCT4 expression in breast cancer tissues and cells. Cell proliferation assays and mouse models were applied to determine the effects of OCT4 on breast cancer cell proliferation. DNMT1 inhibitors, ChIP, CoIP, IHC and ERα inhibitors were used to explore the molecular mechanism of OCT4 in breast cancer.
RESULTS: OCT4 was down-regulated in breast cancer tissues, and the overexpression of OCT4 promoted MDA-MB-231 cell proliferation and inhibited the proliferation of MCF-7 cells in vitro and in vivo, respectively. Two DNMT1 inhibitors (5-aza-dC and zebularine) suppressed OCT4-induced MDA-MB-231 cell proliferation through Ras/Raf1/ERK inactivation by targeting ISL1, which is the downstream of DNMT1. In contrast, OCT4 interacted with ERα, decreased DNMT1 expression and inactivated the Ras/Raf1/ERK signalling pathway in MCF-7 cells. Moreover, ERα inhibitor (AZD9496) reversed the suppression of OCT4-induced proliferation in MCF-7 cells via the activation of ERK signalling pathway.
CONCLUSIONS: OCT4 is dependent on ERα to suppress the proliferation of breast cancer cells through DNMT1/ISL1/ERK axis.
Tatiana S, Marta J, Monika M, Pavel VNoonan syndrome from a fetopathologist perspective.
Cesk Patol. 2019; 55(1):48-52 [PubMed
] Related Publications
We present our experience with four cases of fetal autopsies with abnormal prenatal ultrasound findings and suspicion of Noonan syndrome. These were fetuses from the 17th to the 24th age of gestation (GA). In all cases, prenatal ultrasound examination recorded increased nuchal translucency (NT) and presence of lymphatic neck sacs. Some fetuses showed signs of fetal hydrops and polyhydramnion was found. Similar signs and congenital developmental defects were confirmed in the autopsy examination. These were primarily signs of developing fetal hydrops with increased nuchal edema, in some cases up to the character of cystic hygroma, pleural and abdominal effusions, congenital heart and kidney defects, skeletal defects and facial dysmorphism. A karyotype was examined in all cases without chromosome aneuploidy. The diagnosis of NS was confimed by subsequent genetic analysis of causal gene mutations (mainly PTPN11, KRAS, RAF 1,). Our cases demonstrate a wide range of signs of prenatal presentation of this syndrome. Because of wide differential diagnosis, summarizing prenatal ultrasound findings, autopsy examination and molecular genetic testing is essential.
García-Vázquez R, Marchat LA, Ruíz-García E, et al.MicroRNA-143 is Associated With Pathological Complete Response and Regulates Multiple Signaling Proteins in Breast Cancer.
Technol Cancer Res Treat. 2019; 18:1533033819827309 [PubMed
] Free Access to Full Article Related Publications
Almost 55% to 80% of patients with breast cancer have an unfavorable pathological complete response to chemotherapy. MicroRNAs are small noncoding RNAs involved in cancer progression; however, their utility as predictors of pathological complete response to neoadjuvant chemotherapy is unclear. Here, we investigated if miR-143 could discriminate between pathological complete response and no-polymerase chain reaction of patients with locally advanced triple negative breast cancer that have received a fluorouracil-cisplatin/paclitaxel-based neoadjuvant treatment. Data showed that miR-143 exhibited a significant low expression ( P < .0006) in patients that achieved pathological complete response in comparison to nonresponder group. Receiver operating characteristic curve analysis suggested that miR-143 could be a good predictor of pathological complete response (area under curve = 0.849, P < .0006). Moreover, Kaplan-Meier analysis indicated that before neoadjuvant therapy low levels of miR-143 were associated to increased disease free survival. To gain insights into cellular functions of miR-143, we firstly showed that miR-143 was severely repressed in breast cancer cell lines and tumors in comparison to normal mammary cells and tissues. Ectopic restoration of miR-143 using RNA mimics inhibited both cell proliferation and migration and sensitized breast cancer cells to cisplatin therapy in vitro. To decipher the signaling networks regulated by miR-143, we used a high-throughput enzyme-linked immunosorbent assay-based phosphorylation antibody array. Phospho-proteomic profiling revealed that miR-143 coordinately reduced the protein levels and phosphorylation status of multiple oncoproteins involved in AKT, WNT/β-catenin, SAPK/JNK, FAK, and JAK/STAT signaling pathways. Moreover, low miR-143 and high GSK3-β, RAF1, paxillin, and p21CIP1 expression levels in a large cohort of patients with breast cancer were associated with worst outcome. In summary, miR-143 could be a potential predictor of response to neoadjuvant therapy and it may function as a divergent regulator of diverse signaling networks to suppress cell proliferation and migration in breast cancer.
Köhler M, Ehrenfeld S, Halbach S, et al.B-Raf deficiency impairs tumor initiation and progression in a murine breast cancer model.
Oncogene. 2019; 38(8):1324-1339 [PubMed
] Related Publications
Copy number gains, point mutations and epigenetic silencing events are increasingly observed in genes encoding elements of the Ras/Raf/MEK/ERK signaling axis in human breast cancer. The three Raf kinases A-Raf, B-Raf, and Raf-1 have an important role as gatekeepers in ERK pathway activation and are often dysregulated by somatic alterations of their genes or by the aberrant activity of receptor tyrosine kinases (RTKs) and Ras-GTPases. B-Raf represents the most potent Raf isoform and a critical effector downstream of RTKs and RAS proteins. Aberrant RTK signaling is mimicked by the polyoma middle T antigen (PyMT), which activates various oncogenic signaling pathways, incl. the RAS/ERK axis, in a similar manner as RTKs in human breast cancer. Mammary epithelial cell directed expression of PyMT in mice by the MMTV-PyMT transgene induces mammary hyperplasia progressing over adenoma to metastatic breast cancer with an almost complete penetrance. To understand the functional role of B-Raf in this model for luminal type B breast cancer, we crossed MMTV-PyMT mice with animals that either lack B-Raf expression in the mammary gland or express the signaling impaired B-Raf
Esophageal cancer is the eighth most common form of cancer worldwide, and esophageal squamous cell carcinoma (ESCC) is a major type of esophageal cancer that arises from epithelial cells of the esophagus. Local lymph node metastasis (LNM) is a typical sign of failure for ESCC clinical treatments, and a link has been established between LNM and the aberrant expression of specific biomarkers. In this review, we summarize what is known about nine factors significantly associated with LNM in ESCC patients: phosphatase and tensin homolog (PTEN), mucin 1, vascular endothelial growth factor-C, tumor necrosis factor alpha-induced protein 8 (TNFAIP8), Raf-1 kinase inhibitory protein, stathmin (STMN1), metastasis-associated protein 1, caveolin-1, and interferon-induced transmembrane protein 3. The function of these nine proteins involves four major mechanisms: tumor cell proliferation, tumor cell migration and invasion, epithelium-mesenchymal transition, and chemosensitivity. The roles of PTEN, STMN1, and TNFAIP8 involve at least two of these mechanisms, and we suggest that they are possible biomarkers for predicting LNM in ESCC. However, further retrospective research into PTEN, STMN1, and TNFAIP8 is needed to test their possibilities as indicators.
Lung cancer is the leading cause of cancer-related mortality worldwide, characterized by uncontrolled proliferation and metastasis of lung cancer cells. Tumor angiogenesis plays a key role in proliferation and metastasis in cancers, and is an essential component in microenvironment. It has been reported that long non-coding RNA FBXL19-AS1 plays an oncogenic role in colorectal cancer. However, the molecular mechanism of FBXL19-AS1 in lung cancer has not been fully elucidated. In the present study, we found that FBXL19-AS1 expression was up-regulated in lung cancer tissues and cell lines. FBXL19-AS1 knockdown inhibited cell proliferation, migration, invasion, and angiogenesis in lung cancer cells. Molecular mechanism exploration uncovered that FBXL19-AS1 acted as a molecular sponge of miR-431-5p and that RAF1 was a downstream target of miR-431-5p in lung cancer. Moreover, there was a negative association between miR-431-5p expression and FBXL19-AS1 or RAF1 expression in tumor tissues. Through rescue experiments, we discovered that overexpression of RAF1 partially rescued FBXL19-AS1 knockdown-mediated inhibition of angiogenesis and progression in lung cancer. Together, these results indicated that FBXL19-AS1 was involved in progression and angiogenesis in lung cancer by targeting miR-431-5p/RAF1 axis, which provided a new insight into the therapeutic strategies of lung cancer.
Dong Z, Huang K, Liao B, et al.Prediction of sorafenib treatment-related gene expression for hepatocellular carcinoma: preoperative MRI and histopathological correlation.
Eur Radiol. 2019; 29(5):2272-2282 [PubMed
] Related Publications
PURPOSE: To investigate the feasibility of prediction for targeted therapy-related gene expression in hepatocellular carcinoma (HCC) using preoperative gadoxetic acid-enhanced magnetic resonance imaging (MRI).
MATERIALS AND METHODS: Ninety-one patients (81 men, mean age 53.9 ± 12 years) with solitary HCC who underwent preoperative enhanced MRI were retrospectively analyzed. Features including tumor size, signal homogeneity, tumor capsule, tumor margin, intratumoral vessels, peritumor enhancement, peritumor hypointensity, signal intensity ratio on DWI, T1 relaxation times, and the reduction rate between pre- and post-contrast enhancement images were assessed. The operation and histopathological evaluation were performed within 2 weeks after MRI examination (mean time 7 days). The expression levels of BRAF, RAF1, VEGFR2, and VEGFR3 were evaluated. The associations between these imaging features and gene expression levels were investigated.
RESULTS: Tumor incomplete capsules or non-capsules (p = 0.001) and intratumoral vessels (p = 0.002) were significantly associated with BRAF expression, and tumor incomplete capsules or non-capsules (p = 0.001) and intratumoral vessels (p = 0.013) with RAF1 expression. There was no significant association between the expression of VEGFR2, VEGFR3, and all examined MRI features. Multivariate logistic regression showed that incomplete tumor capsule (p = 0.002) and non-capsule (p = 0.004) were independent risk factors of HCC with high BRAF expression; incomplete tumor capsule (p < 0.001) and non-capsule (p = 0.040) were independent risk factors of HCC with high RAF1 expression.
CONCLUSION: The presence of incomplete capsule or intratumoral vessels and the absence of capsule are potential indicators of high BRAF and RAF1 expression. Gadoxetic acid-enhanced MRI may facilitate the choice of gene therapy for patients with HCC.
KEY POINTS: • Incomplete tumor capsule and non-capsule were independent risk factors of HCC with high BRAF and RAF1 expression. • The presence of intratumoral vessels was a potential indicator of high BRAF and RAF1 expression. • Gadoxetic acid-enhanced MRI may be a predictor of efficacy of treatment with sorafenib.
Gao D, Qi X, Zhang X, et al.hsa_circRNA_0006528 as a competing endogenous RNA promotes human breast cancer progression by sponging miR-7-5p and activating the MAPK/ERK signaling pathway.
Mol Carcinog. 2019; 58(4):554-564 [PubMed
] Related Publications
Emerging research has indicated that circular RNAs (circRNAs), a novel class of non-coding RNAs, play a vital role in human tumorigenesis and progression. Our previous results suggested that hsa_circ_0006528 (circ_0006528), a circRNA with an unknown function, mediates adriamycin resistance in human breast cancer cells. However, the role of circ_0006528 in breast cancer progression remains unknown. Here, we investigated the probable involvement of circ_0006528 in breast cancer. We analyzed a cohort of 97 patients and found that circ_0006528 expression was significantly upregulated in human breast cancer tissues compared with that in adjacent non-tumorous tissues and was significantly associated with advanced tumor-node-metastasis (TNM) stage and poor prognosis. In addition, we found that in breast cancer cells, circ_0006528 could promote DNA synthesis and cell proliferation, invasion, and migration. Downregulating circ_0006528 induced G2 phase arrest and cell apoptosis. Further mechanistic studies revealed that circ_0006528 could sponge endogenous miR-7-5p and inhibit its activity. We also identified Raf1, which activates the MAPK/ERK signaling pathway, as a target of miR-7-5p and determined that circ_0006528 promotes breast cancer growth, invasion, and migration by promoting the expression of Raf1 and activates the MAPK/ERK pathway. Thus, this study provides the first evidence of the circ_0006528/miR-7-5p/Raf1/MEK/ERK regulatory network in the development of breast cancer and suggests that circ_0006528 is a potential therapeutic target and prognostic predictor for breast cancer.
Apanovich NV, Peters MV, Apanovich PV, et al.Association of Target Therapy Gene Expression with Metastasizing of Clear-Cell Renal Cell Carcinoma.
Bull Exp Biol Med. 2018; 166(2):257-259 [PubMed
] Related Publications
We analyzed association of the levels of VEGFA, RAF1, and mTOR gene expression in the tissue of clear-cell renal cell carcinoma (ccRCC) with tumor metastasizing. Significant association with metastases was found only for VEGFA gene: OR=6.641, 95%CI=2.111-20.696. The risk of metastasis associated with reduced expression of VEGFA gene - 2.467, 95%CI=1.238-4.915. An association of VEGFA gene expression with the time to the metastasis appearance was revealed (p=0.0005). Reduced expression of the VEGFA gene is associated with reduction of the time to metastasis appearance; the median of this time is shifted from 46 to 2 months. Analysis of tumor samples with reduced expression of the VEGFA gene revealed association of increased expression of RAF1 (p=0.003) and mTOR genes (p=0.038) with metastasis.
Kleemann M, Schneider H, Unger K, et al.Induction of apoptosis in ovarian cancer cells by miR-493-3p directly targeting AKT2, STK38L, HMGA2, ETS1 and E2F5.
Cell Mol Life Sci. 2019; 76(3):539-559 [PubMed
] Related Publications
Apoptosis is a form of directed programmed cell death with a tightly regulated signalling cascade for the destruction of single cells. MicroRNAs (miRNAs) play an important role as fine tuners in the regulation of apoptotic processes. MiR-493-3p mimic transfection leads to the induction of apoptosis causing the breakdown of mitochondrial membrane potential and the activation of Caspases resulting in the fragmentation of DNA in several ovarian carcinoma cell lines. Ovarian cancer shows with its pronounced heterogeneity a very high death-to-incidence ratio. A target gene analysis for miR-493-3p was performed for the investigation of underlying molecular mechanisms involved in apoptosis signalling pathways. Elevated miR-493-3p levels downregulated the mRNA and protein expression levels of Serine/Threonine Kinase 38 Like (STK38L), High Mobility Group AT-Hook 2 (HMGA2) and AKT Serine/Threonine Kinase 2 (AKT2) by direct binding as demonstrated by luciferase reporter assays. Notably, the protein expression of RAF1 Proto-Oncogene, Serine/Threonine Kinase (RAF1) was almost completely downregulated by miR-493-3p. This interaction, however, was indirect and regulated by STK38L phosphorylation. In addition, RAF1 transcription was diminished as a result of reduced transcription of ETS proto-oncogene 1 (ETS1), another direct target of miR-493-3p. Taken together, our observations have uncovered the apoptosis inducing potential of miR-493-3p through its regulation of multiple target genes participating in the extrinsic and intrinsic apoptosis pathway.
Song J, Yuan C, Yang J, et al.Novel flavagline-like compounds with potent Fli-1 inhibitory activity suppress diverse types of leukemia.
FEBS J. 2018; 285(24):4631-4645 [PubMed
] Related Publications
E26 transformation-specific (ETS) gene family contains a common DNA-binding domain, the ETS domain, responsible for sequence-specific DNA recognition on target promoters. The Fli-1 oncogene, a member of ETS gene family, plays a critical role in hematopoiesis and is overexpressed in diverse hematological malignancies. This ETS transcription factor regulates genes controlling several hallmarks of cancer and thus represents an excellent target for cancer therapy. By screening compounds isolated from the medicinal plant Dysoxylum binectariferum in China, we identified two chemically related flavagline-like compounds including 4'-demethoxy-3',4'-methylenedioxyrocaglaol and rocaglaol that strongly inhibited Fli-1 transactivation ability. These compounds altered expression of Fli-1 target genes including GATA1, EKLF, SHIP1, and BCL2. Consequently, the flavagline-like compounds suppressed proliferation, induced apoptosis, and promoted erythroid differentiation of leukemic cells in culture. These compounds also suppressed erythroleukemogenesis in vivo in a Fli-1-driven mouse model. Mechanistically, the compounds blocked c-Raf-MEK-MAPK/ERK signaling, reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), and inhibited Fli-1 protein synthesis. Consistent with its high expression in myelomas, B-cell lymphoma, and B chronic lymphocytic leukemia (B-CLL), pharmacological inhibition of Fli-1 by the flavagline-like compounds or genetic knock-down via shRNA significantly hindered proliferation of corresponding cell lines and patients' samples. These results uncover a critical role of Fli-1 in growth and survival of various hematological malignancies and point to flavagline-like agents as lead compounds for the development of anti-Fli-1 drugs to treat leukemias/lymphomas overexpressing Fli-1.
Li G, Wang K, Li Y, et al.Role of eIF3a in 4-amino-2-trifluoromethyl-phenyl retinate-induced cell differentiation in human chronic myeloid leukemia K562 cells.
Gene. 2019; 683:195-209 [PubMed
] Related Publications
4-amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, has been demonstrated its anti-tumor effect through inducing differentiation and inhibiting proliferation. Eukaryotic initiation factor 3a (eIF3a) plays a critical role in affecting tumor cell proliferation and differentiation. However, whether eIF3a is implicated in chronic myeloid leukemia cells differentiation remains unclear. Our results demonstrated that eIF3a could be suppressed by ATPR in K562 cells. The results also confirmed that ATPR could arrest cell cycle in G0/G1 phase and induced differentiation. Moreover, over-expression of eIF3a promoted not only protein expression of c-myc and cyclin D1, but also prevented the expression of p-Raf-1, p-ERK and the myeloid differentiation markers CD11b and CD14 and had an influence on inducing the morphologic mature. However, silencing eIF3a expression by small interfering RNA could have an adverse effect on K562 cells. In addition, PD98059 (a MEK inhibitor) could block cell differentiation of CML cells and contributed to the expression of c-myc and cyclin D1. In conclusion, these results indicated that eIF3a played an important role in ATPR-induced cell differentiation in K562 cells, its mechanism might be related to its ability in regulating the activation of ERK1/2 signaling pathway in vitro.
BACKGROUND: RAF family activating fusions have been described as a potentially targetable molecular finding in a subset of soft tissue sarcomas. To further expand upon the landscape of this genetic feature, we describe a novel MTAP-RAF1 activating fusion identified in a S100 positive soft tissue sarcoma.
CASE PRESENTATION: A 51 year old man underwent excision of a soft tissue mass in his foot. Pathology revealed a spindle cell neoplasm with S100 positivity, ultimately classified as a soft tissue sarcoma, not otherwise specified. Comprehensive molecular profiling was performed to help establish the diagnosis and revealed a novel MTAP-RAF1 fusion that includes the tyrosine kinase domain of RAF1.
CONCLUSIONS: Our report adds to the spectrum of fusion-driven RAF activation observed in soft tissue sarcomas and lends additional evidence that RAF activation plays an important role in some soft tissue sarcomas. Identification of novel fusions involving the MAPK/ERK pathway in sarcomas may provide new avenues for precision medicine strategies involving targeted kinase inhibitors.
The complexities of molecular signaling in cancer cells have been hypothesized to mediate cross-network alterations of oncogenic processes such as uncontrolled cell growth, proliferation, acquisition of epithelial-to-mesenchymal transition (EMT) markers, and resistance to cytotoxic therapies. The two biochemically exclusive processes/proteins examined in the present review are the metastasis suppressor Raf-1 kinase inhibitory protein (RKIP) and the cell-intrinsic system of macroautophagy (hereafter referred to as autophagy). RKIP is poorly expressed in human cancer tissues, and low expression levels are correlated with high incidence of tumor growth, metastasis, poor treatment efficacy, and poor prognoses in cancer patients. By comparison, autophagy is a conserved cytoprotective degradation pathway that has been shown to influence the acquisition of resistance to hypoxia and nutrient depletion as well as the regulation of chemo-immuno-resistance and apoptotic evasion. Evidently, a broad library of cancer-relevant studies exists for RKIP and autophagy, although reports of the interactions between pathways involving RKIP and autophagy have been relatively sparse. To circumvent this limitation, the coordinate regulatory and effector mechanisms were examined for both RKIP and autophagy. Here, we propose three putative pathways that demonstrate the inherent pleiotropism and relevance of RKIP and the microtubule-associated protein 1 light chain 3 (MAP1LC3, LC3) on cell growth, proliferation, senescence, and EMT, among the hallmarks of cancer. Our findings suggest that signaling modules involving p53, signal transducer and activator of transcription 3 (STAT3), nuclear factor-κB (NF-κB), and Snail highlight the novel roles for RKIP in the control of autophagy and vice versa. The suggested potential crosstalk mechanisms are new areas of research in which to further study RKIP and autophagy in cancer models. These should lead to novel prognostic motifs and will provide alternative therapeutic strategies for the treatment of unresponsive aggressive cancer types.
Bologna-Molina R, Ogawa I, Mosqueda-Taylor A, et al.Detection of MAPK/ERK pathway proteins and KRAS mutations in adenomatoid odontogenic tumors.
Oral Dis. 2019; 25(2):481-487 [PubMed
] Related Publications
OBJECTIVE: This study aimed to assess the frequency of KRAS mutation and its association with the presence of the MAPK/ERK signaling pathway proteins in adenomatoid odontogenic tumors.
STUDY DESIGN: Paraffin-embedded tissue samples from nine cases of adenomatoid odontogenic tumor were used. Genomic DNA was extracted from each sample; in one case, genetic mutations in 50 cancer-associated genes were examined by next-generation sequencing. Hotspot mutations in the RAS family were analyzed by Luminex assay using the remaining eight cases. Subsequently, immunohistochemistry for KRAS, CRAF, BRAF, EGFR, ERK, MEK, and BRAFV600E was performed.
RESULTS: A KRAS G12D missense mutation was detected in the DNA sequence of the tumor cells, but it was not detected in the stromal tissue. KRAS G12V and KRAS G12R mutations were detected in two and four cases, respectively. For immunohistochemistry, all the cases were EGFR, KRAS, BRAF, CRAF positive, one case was ERK negative,and one case was MEK and ERK negative, all the other remaining cases were MEK and ERK positive.
CONCLUSION: KRAS mutation at codon 12 and the presence of MAPK/ERK pathway proteins were detected suggesting their association with tumorigenesis of adenomatoid odontogenic tumors.
Suurmeijer AJH, Dickson BC, Swanson D, et al.A novel group of spindle cell tumors defined by S100 and CD34 co-expression shows recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes.
Genes Chromosomes Cancer. 2018; 57(12):611-621 [PubMed
] Related Publications
Tumors characterized by co-expression of S100 and CD34, in the absence of SOX10, remain difficult to classify. Triggered by a few index cases with monomorphic cytomorphology and distinctive stromal and perivascular hyalinization, immunopositivity for S100 and CD34, and RAF1 and NTRK1 fusions, the authors undertook a systematic review of tumors with similar features. Most of the cases selected were previously diagnosed as low-grade malignant peripheral nerve sheath tumors, while others were deemed unclassified. The tumors were studied with targeted RNA sequencing and/or FISH. A total of 25 cases (15 adults and 10 children) with kinase fusions were identified, including 8 cases involving RAF1, 2 BRAF, 14 NTRK1, and 1 NTRK2 gene rearrangements. Most tumors showed a monomorphic spindle cell proliferation with stromal and perivascular keloidal collagen, in a patternless architecture, with only occasional scattered pleomorphic or multinucleated cells. Most cases showed low cellularity, a low mitotic count, and absence of necrosis. Although a subset showed overlap with lipofibromatosis-like neural tumors, the study group showed distinctive hyalinization and overt malignant features, such as highly cellular fascicular growth and primitive appearance. All tumors showed co-expression of S100 and CD34, ranging from focal to diffuse. SOX10 was negative in all cases. NTRK1 immunohistochemistry showed high levels of expression in all tumors with NTRK1 gene rearrangements. H3K27me3 expression performed in a subset of cases was retained. These findings together with the recurrent gene fusions in RAF1, BRAF, and NTRK1/2 kinases suggest a distinct molecular tumor subtype with consistent S100 and CD34 immunoreactivity.
Melatonin is the main pineal hormone that relays light/dark-cycle information to the circadian system. Recent studies have examined the intrinsic antitumor activity of melatonin in various cancers, including hepatocellular carcinoma (HCC), the primary life-threatening malignancy in both sexes in Taiwan. However, the detailed regulatory mechanisms underlying melatonin's anti-HCC activity remain incompletely understood. Here, we investigated the mechanisms by which the anti-HCC activity of melatonin is regulated. Human hepatoma cell lines were treated with 1 and 2 mM melatonin, and functional assays were used to dissect melatonin's antitumor effect in HCC; small-RNA sequencing was performed to identify the microRNAs (miRNAs) involved in the anti-HCC activity of melatonin; and quantitative RT-PCR and Western blotting were used to elucidate how miRNAs regulate melatonin-mediated HCC suppression. Melatonin treatment at both doses strongly inhibited the proliferation, migration and invasion capacities of Huh7 and HepG2 cell lines, and melatonin treatment markedly induced the expression of the miRNA let7i-3p in cells. Notably, transfection of cells with a let7i-3p mimic drastically reduced RAF1 expression and activation of mitogen-activated protein kinase signaling downstream from RAF1, and rescue-assay results demonstrated that melatonin inhibited HCC progression by modulating let7i-3p-mediated RAF1 suppression. Our findings support the view that melatonin treatment holds considerable promise as a therapy for HCC.
RAS GTPases are frequently mutated in human cancer. H- and NRAS isoforms are distributed over both plasma-membrane and endomembranes, including the Golgi complex, but how this organizational context contributes to cellular transformation is unknown. Here we show that RAS at the Golgi is selectively activated by apoptogenic stimuli and antagonizes cell survival by suppressing ERK activity through the induction of PTPRκ, which targets CRAF for dephosphorylation. Consistently, in contrast to what occurs at the plasma-membrane, RAS at the Golgi cannot induce melanoma in zebrafish. Inactivation of PTPRκ, which occurs frequently in human melanoma, often coincident with TP53 inactivation, accelerates RAS-ERK pathway-driven melanomagenesis in zebrafish. Likewise, tp53 disruption in zebrafish facilitates oncogenesis driven by RAS from the Golgi complex. Thus, RAS oncogenic potential is strictly dependent on its sublocalization, with Golgi complex-located RAS antagonizing tumor development.
BACKGROUND: Development of distant metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which includes dissemination of cancer cells from the primary tumor to secondary organs. NOTCH developmental signaling plays a critical role in promoting epithelial-to-mesenchymal transition, tumor stemness, and metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive.
METHODS: We have established metastatic xenografts expressing high endogenous levels of NOTCH3 using estrogen receptor alpha-positive (ERα
RESULTS: In this study, we identified an association between NOTCH3 expression and development of metastases in ERα
CONCLUSIONS: These findings demonstrate the key role of NOTCH3 oncogenic signaling in the genesis of breast cancer metastasis and provide a compelling preclinical rationale for the design of novel therapeutic strategies that will selectively target NOTCH3 to halt metastatic seeding and to improve the clinical outcomes of patients with breast cancer.
Cancer is a major public health problem around the globe. This disorder is affected by alterations in multiple physiological processes, and oxidative stress has been etiologically implicated in its pathogenesis. Glioblastoma (GBM) is considered the most common and aggressive brain tumor with poor prognosis despite recent improvements in surgical, radiation, and chemotherapy-based treatment approaches. The purpose of this study was to evaluate antitumor activity from
Phillips JJ, Gong H, Chen K, et al.The genetic landscape of anaplastic pleomorphic xanthoastrocytoma.
Brain Pathol. 2019; 29(1):85-96 [PubMed
] Related Publications
Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. We performed comprehensive genomic profiling on a set of 23 PXAs from 19 patients, including 15 with anaplastic PXA. Four patients had tumor tissue from multiple recurrences, including two with anaplastic progression. We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements. The third most commonly altered gene in anaplastic PXA was TERT, with 47% (7/15) harboring TERT alterations, either gene amplification (n = 2) or promoter hotspot mutation (n = 5). In tumor pairs analyzed before and after anaplastic progression, two had increased copy number alterations and one had TERT promoter mutation at recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX, PTEN, and BCL6. All PXA in this cohort were IDH and histone H3 wildtype, and did not contain alterations in EGFR. Genetic profiling performed on six regions from the same tumor identified intratumoral genomic heterogeneity, likely reflecting clonal evolution during tumor progression. Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.
BACKGROUND: Expression of COP9 signalosome subunit 3 (COPS3), an oncogene overexpressed in osteosarcoma, has been demonstrated to be significantly correlated with tumor metastasis. However, the underlying mechanism by which COPS3 promotes metastasis of osteosarcoma and its role in autophagy remain unknown.
METHODS: The expression of COPS3 was detected in primary osteosarcoma tissues and matching lung metastasis tissues by immunohistochemistry (IHC). The effect of COPS3 on the metastasis of osteosarcoma cells was investigated by transwell, wound healing assays and animal studies. Indicated proteins was analyzed by western blotting when COPS3 was knockdown or overexpressed. The COPS3 Interacting protein was determined by immunoprecipitation assay. The relationship between COPS3 and autophagy was detected by western blotting and immunofluorescence.
RESULTS: We found that knockdown of COPS3 significantly reduced the lung metastasis of osteosarcoma cells in a mouse model, coinciding with downregulation of mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) signaling. The silencing of COPS3 also inhibited the epithelial-mesenchymal transition (EMT) through the 90 kDa ribosomal S6 kinases (RSK), a family of signal transduction proteins downstream of MEK/ERK. Reciprocal immunoprecipitation assays revealed that COPS3 directly interacts with Raf-1, an upstream regulator of MEK/ERK. Surprisingly, Beclin1, an important autophagic protein, appeared in the COPS3-immunoprecipitates, along with the autophagic markers LC3-I and LC3-II. Loss of COPS3 completely inhibited H
CONCLUSIONS: Taken together, these data reveal a novel function of COPS3 in the regulation of autophagy and highlight the relationship between autophagy and metastasis in osteosarcoma cells.
Qin AD, Liu XX, Li J, et al.[The effects of microRNA-7 on proliferation and invasion of hepatocellular carcinoma HepG2 cells].
Zhonghua Zhong Liu Za Zhi. 2018; 40(6):406-411 [PubMed
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Wu GJ, Pen J, Huang Y, et al.KAP1 inhibits the Raf-MEK-ERK pathway to promote tumorigenesis in A549 lung cancer cells.
Mol Carcinog. 2018; 57(10):1396-1407 [PubMed
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Aberrant activation of the Raf-MEK-ERK pathway has frequently been associated with various cancers, especially lung cancer. However, the key regulators of this pathway are largely unknown. Using functional proteomics screening, we found that KAP1 interacts with c-Raf. Knocking out KAP1 decreased c-Raf phosphorylation at serine 259 and increased its phosphorylation at serine 338, which activated MEK and ERK. We detected higher KAP1 expression in lung cancer tissues than in normal peri-tumoral tissues. KAP1 knockdown arrested A549 lung cancer cells in the G0/G1 phase of the cell cycle and attenuated cell growth, metastasis, the epithelial-mesenchymal transition, angiogenesis, stemness, and colony formation. Furthermore, knocking out KAP1 remarkably increased the susceptibility of A549 cells to the anti-cancer drug 5-Fluorouracil, which correlated with increasing ERK phosphorylation. In vivo xenograft experiments suggested that KAP1 deficiency significantly decreases the tumorigenicity of A549 cells. Taken together, our findings indicate that KAP1 acts as a key module in the c-Raf-interactome complex and regulates lung cancer development through the Raf-MEK-ERK pathway. Therefore, KAP1 may represent a potential diagnosis biomarker and new treatment target for lung cancer.
Wang Y, Lin X, Fu X, et al.Long non-coding RNA BANCR regulates cancer stem cell markers in papillary thyroid cancer via the RAF/MEK/ERK signaling pathway.
Oncol Rep. 2018; 40(2):859-866 [PubMed
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Thyroid cancer is one of the most common malignant tumors of the endocrine system. Among all thyroid cancers, papillary thyroid carcinoma (PTC) is the most common type. The BRAF-activated non-coding RNA (BANCR) is a 693-bp nucleotide transcript which was first identified in melanoma. However, the role of BANCR in the development of thyroid cancer remains unclear. Therefore, the present study investigated the potential involvement of BANCR in the development of thyroid cancer in vitro using patient tissue samples and a panel of thyroid cancer cell lines, and in vivo using a xenograft mouse model. We observed that BANCR was expressed at a higher level in human thyroid tumor tissues than that noted in the adjacent normal tissues. The expression level of BANCR differed between cultured thyroid cancer cell lines; BANCR expression was lower in the BCPAP cell line than that observed in the CAL-62, WRO and FTC-133 cell lines. Western blot analysis and flow cytometry revealed that overexpression of BANCR in the BCPAP cell line resulted in increased expression of the cancer stem cell markers, LGR5 and EpCAM. Single-clone formation experiments showed that upregulated expression of BANCR in the BCPAP cell line promoted an increase in the number of clones formed. Similarly, in microsphere formation experiments, overexpression of BANCR resulted in increased number and size of microspheres compared with the control cell line. Western blotting experiments showed that BANCR overexpression in BCPAP upregulated the expression of phosphorylated c-Raf, MEK1/2 and ERK1/2. Inhibition of c-Raf via U0126 decreased the expression of LGR5 and EpCAM, as well as phosphorylated levels of c-Raf, MEK1/2 and ERK1/2 in the BCPAP cells, compared to levels in the DMSO controls. In the xenograft mouse model, BANCR overexpression in the thyroid cancer cells significantly increased tumor growth. Taken together, these results suggest that BANCR plays a role in PTC development by regulating the expression of cancer stem cell markers LGR5 and EpCAM via the c-Raf/MEK/ERK signaling pathway. Therefore, BANCR may be used as a novel prognostic marker for PTC.
Ganglioglioma is the most common epilepsy-associated neoplasm that accounts for approximately 2% of all primary brain tumors. While a subset of gangliogliomas are known to harbor the activating p.V600E mutation in the BRAF oncogene, the genetic alterations responsible for the remainder are largely unknown, as is the spectrum of any additional cooperating gene mutations or copy number alterations. We performed targeted next-generation sequencing that provides comprehensive assessment of mutations, gene fusions, and copy number alterations on a cohort of 40 gangliogliomas. Thirty-six harbored mutations predicted to activate the MAP kinase signaling pathway, including 18 with BRAF p.V600E mutation, 5 with variant BRAF mutation (including 4 cases with novel in-frame insertions at p.R506 in the β3-αC loop of the kinase domain), 4 with BRAF fusion, 2 with KRAS mutation, 1 with RAF1 fusion, 1 with biallelic NF1 mutation, and 5 with FGFR1/2 alterations. Three gangliogliomas with BRAF p.V600E mutation had concurrent CDKN2A homozygous deletion and one additionally harbored a subclonal mutation in PTEN. Otherwise, no additional pathogenic mutations, fusions, amplifications, or deletions were identified in any of the other tumors. Amongst the 4 gangliogliomas without canonical MAP kinase pathway alterations identified, one epilepsy-associated tumor in the temporal lobe of a young child was found to harbor a novel ABL2-GAB2 gene fusion. The underlying genetic alterations did not show significant association with patient age or disease progression/recurrence in this cohort. Together, this study highlights that ganglioglioma is characterized by genetic alterations that activate the MAP kinase pathway, with only a small subset of cases that harbor additional pathogenic alterations such as CDKN2A deletion.
Kim JS, Choi GH, Jung Y, et al.Downregulation of Raf-1 kinase inhibitory protein as a sorafenib resistance mechanism in hepatocellular carcinoma cell lines.
J Cancer Res Clin Oncol. 2018; 144(8):1487-1501 [PubMed
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PURPOSE: Although sorafenib enhances overall survival, sorafenib resistance has been reported to be a significant limiting factor for improved prognosis in patients with hepatocellular carcinoma (HCC). Therefore, it is important to identify the mechanism of sorafenib resistance. This study aimed to identify the causative factor of sorafenib resistance and suggest methods for overcoming it.
METHODS: The sensitivity to sorafenib was compared in human HCC cell lines and patient-derived HCC primary cells. Based on its cytotoxicity, signaling pathways altered by sorafenib and the causative factors were examined through assays. The mechanism by which sorafenib modified the sorafenib-resistance inducer through gene or protein expression or stability was also investigated. We also designed a treatment option to overcome sorafenib resistance.
RESULTS: Sorafenib activated the Raf/MEK/ERK pathway and caused sorafenib resistance in HCC cell lines and patient-derived HCC primary cells. Sorafenib reactivated the MAPK pathway by down-regulating RKIP at the post-translational level. Knockdown of RKIP increased phosphorylated ERK and thus suppressed sorafenib-mediated cell death. We also found that sorafenib-reactivated ERK maybe an attractive target for second-line therapy for patients with sorafenib resistance. Sequential combination treatment with sorafenib and PD98059 significantly reduced the viability and proliferation of sorafenib-resistant cells, while their increasing apoptosis efficacy.
CONCLUSION: Reactivation of the Raf/MEK/ERK pathway through aberrant expression of RKIP is one of the mechanisms behind sorafenib resistance in HCC. Sequential combination treatment with sorafenib and PD98059 could provide a new strategy to overcome sorafenib resistance in future clinical studies.
Kim G, Kim JY, Lim SC, et al.SUV39H1/DNMT3A-dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development.
FASEB J. 2018; 32(10):5647-5660 [PubMed
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Melanoma is among the most aggressive and treatment-resistant human cancers. Aberrant histone H3 methylation at Lys 9 (H3K9) correlates with carcinogenic gene silencing, but the significance of suppressor of variegation 3-9 homolog 1 (SUV39H1), an H3K9-specific methyltransferase, in melanoma initiation and progression remains unclear. Here, we show that SUV39H1-mediated H3K9 trimethylation facilitates retinoblastoma ( RB) 1 promoter CpG island methylation by interacting with DNA methyltransferase 3A and decreasing RB mRNA and protein in melanoma cells. Reduced RB abundance, in turn, impairs E2F1 transcriptional inhibition, leading to increased peptidyl-prolyl cis-trans isomerase never-in-mitosis A (NIMA)-interacting 1 (PIN1) levels, human keratinocyte neoplastic cell transformation, and melanoma tumorigenesis via enhanced rapidly accelerated fibrosarcoma 1(RAF1)-MEK-ERK signaling pathway activation. In a synergistic model with B16-F1 murine melanoma cells, SUV39H1 and PIN1 overexpression increased melanoma growth, which was abrogated by their inhibition in SUV39H1-overexpressing B16-F1 mice. SUV39H1 also positively correlated with PIN1 expression in human melanoma. Our studies establish SUV39H1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis.-Kim, G., Kim, J.-Y., Lim, S.-C., Lee, K. Y., Kim, O., Choi, H. S. SUV39H1/DNMT3A-dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development.