Research IndicatorsGraph generated 31 August 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 31 August, 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: CCND1 (cancer-related)
Fasihi A, Soltani BM, Ranjbaran ZS, et al.Hsa-miR-942 fingerprint in colorectal cancer through Wnt signaling pathway.
Gene. 2019; 712:143958 [PubMed
] Related Publications
The Wnt signaling pathway has been identified for its function in carcinogenesis and embryonic development. It is known to play a vital role in the initiation and development of colorectal cancer (CRC). Therefore, it is of great importance for CRC research to illuminate the mechanisms which regulate Wnt pathway activity. Here, we intended to examine the effect of hsa-miR-942 (miR-942) on the Wnt signaling activity, cell cycle progression, and its expression in CRC tissues. RT-qPCR results indicated that miR-942 is significantly upregulated in colorectal cancer. Then, overexpression of miR-942 promoted, whereas its inhibition decreased the Wnt signaling activity, detected by RT-qPCR and Top/Fop flash assay. Inhibition of Wnt signaling by using PNU-74654 or IWP-2 small molecules indicated that miR-942 applies its effect to the β-catenin degradation complex level. Then, RT-qPCR and dual luciferase assay showed that miR-942 upregulated Wnt signaling through direct targeting of APC, which is a tumor suppressor in Wnt signaling pathway. Furthermore, the western blotting analysis indicated that β.catenin, as a main member of Wnt signaling pathway is upregulated following the overexpression of miR-942. Finally, miR-942 overexpression resulted in cell cycle progression in SW480 cells. Taken together, our findings established an oncogenic role for miR-942 in CRC and indicated that this miRNA might be a crucial target for CRC therapy.
Kishore C, Sundaram S, Karunagaran DVitamin K3 (menadione) suppresses epithelial-mesenchymal-transition and Wnt signaling pathway in human colorectal cancer cells.
Chem Biol Interact. 2019; 309:108725 [PubMed
] Related Publications
Tumor recurrence and metastasis decrease the survival rate of colorectal cancer (CRC) patients. Menadione reduces the numbers and incidences of 1,2-dimethylhydrazine induced colon tumors in mouse but the mechanism of anticancer activity of menadione in colorectal cancer is not very clear. Since Wnt signaling is constitutively active in CRC and it aggravates the epithelial mesenchymal transition (EMT), the regulation of EMT and Wnt signaling by menadione (vitamin K3) was investigated in CRC cells. Menadione showed cytotoxicity against human CRC cells (SW480 and SW620) and human primary colon cancer cells but was relatively ineffective against the cells from human normal colon (CRL-1790) and human primary colon epithelial cells. Menadione suppressed invasion, migration and epithelial-mesenchymal transition in human CRC cells by upregulating the expression of E-cadherin (CDH1), ZO-1 and downregulating that of N-cadherin (CDH2), Vimentin (VIM), ZEB1, MMP2 and MMP9. Menadione decreased TOPFlash/FOPFlash luciferase activity and expression of several downstream targets of Wnt signaling and coactivators such as β-catenin (CTNNB1), TCF7L2, Bcl9l, p300 (EP300) and cyclin D1 (CCND1) was suppressed. Menadione induced differentiation and increased apoptotic cell population in SubG0 phase of cell cycle in SW480 and SW620 cells. The ability of menadione to suppress EMT, migration, invasion, Wnt signaling, cell proliferation and induce Sub G0 arrest, highlights its potential to be considered for intensive preclinical and clinical investigation in CRC.
The t(11;14)/CCND1-IGH, t(4;14)/NSD2(MMSET)-IGH, and t(14;16)/IGH-MAF gene rearrangements detected by fluorescence in situ hybridization (FISH) are used for risk stratification in patients with multiple myeloma (MM). Compared with conventional FISH techniques using fresh cells, immunohistochemistry (IHC) is much more cost- and time-efficient, and can be readily applied to routinely prepared formalin-fixed, paraffin-embedded (FFPE) materials. In this study, we performed tissue FISH and IHC employing FFPE specimens, and examined the usefulness of IHC as a tool for detecting CCND1, NSD2, and MAF gene rearrangements. CD138 signals were used to identify plasma cells in tissue FISH and IHC analyses. With cohort 1 (n = 70), we performed tissue FISH and subsequently IHC, and determined IHC cut-off points. In this cohort, the sensitivity and specificity for the 3 molecules were ≥.90 and ≥.96, respectively. With cohort 2, using MM cases with an unknown gene status (n = 120), we performed IHC, and the gene status was estimated using the cut-off points determined with cohort 1. The subsequent FISH analysis showed that the sensitivity and specificity for the 3 molecules were ≥.92 and ≥.98, respectively. CCND1, NSD2, and MAF gene rearrangements were estimated accurately by IHC, suggesting that conventional FISH assays can be replaced by IHC.
Forte M, Di Lorenzo M, Iachetta G, et al.Nonylphenol acts on prostate adenocarcinoma cells via estrogen molecular pathways.
Ecotoxicol Environ Saf. 2019; 180:412-419 [PubMed
] Related Publications
Estrogens play a role in the patho-physiology of the prostate. In the present work we studied the effects of nonylphenol (NP), a xenoestrogen, on human adenocarcinoma prostate cells (LNCaP). In order to understand molecular and cellular involvement, we observed the effects on cell cycle and we investigated the expression and the cellular localization of estrogen receptors and gene expression of cyclin D1, ki-67, c-myc, IL-8, IL-1β. We performed the same experiments with 17β-estradiol (E2), the most abundant estrogen circulating in nonpregnant humans in order to compare these two different substances. We demonstrated the ability of 1 × 10
Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer (GC) tumorigenesis. Here, we analysis structural variations (SVs) and mutational signatures via whole-genome sequencing of 168 GCs. Our data demonstrates diverse models of complex SVs operative in GC, which lead to high-level amplification of oncogenes. We find varying proportion of tandem-duplications (TDs) among individuals and identify 24 TD hotspots involving well-established cancer genes such as CCND1, ERBB2 and MYC. Specifically, we nominate a novel hotspot involving the super-enhancer of ZFP36L2 presents in approximately 10% GCs from different cohorts, the oncogenic role of which is further confirmed by experimental data. In addition, our data reveal a mutational signature, specifically occurring in noncoding region, significantly enriched in tumors with cadherin 1 mutations, and associated with poor prognoses. Collectively, our data suggest that TDs might serve as an important mechanism for cancer gene activation and provide a novel signature for stratification.
BACKGROUND: Effector CD8
METHODS: The interactions between T cell activation status and either BRCA1 or CCND1 expression were evaluated using Kaplan-Meier survival curves and multivariate Cox regression models in a public dataset with 1088 breast cancer patients.
RESULTS: Among the patients with low BRCA1 or CCND1 expression, the Activation group showed better overall survival than the Exhaustion group. Adjusted hazards ratios were 0.43 (95% CI: 0.20-0.93) in patients with a low BRCA1 level, and 0.39 (95% CI: 0.19-0.81) in patients with a low CCND1 level, respectively. There was a significant trend in both subgroups (p-trend = 0.011 in the low BRCA1 group, and p-trend = 0.009 in the low CCND1 group). In contrast, there is no significant association in patients with either high BRCA1 or high CCND1 levels. There is a significant interaction between T cell activation status and BRCA1 level (p = 0.009), but not between T cell activation status and CCND1 level (p = 0.135).
CONCLUSIONS: BRCA1 expression modified the effect of T cell activation status on patient survival in breast cancer, suggesting that the existence of neoantigens and the enhancement of neoantigen presentation in combination with immune checkpoint blockade may have synergistic effects on patient outcome.
Liu X, Chen H, Hou Y, et al.Adaptive EGF expression sensitizes pancreatic cancer cells to ionizing radiation through activation of the cyclin D1/P53/PARP pathway.
Int J Oncol. 2019; 54(4):1466-1480 [PubMed
] Related Publications
It is well-known that the activation status of the P53, signal transducer and activator of transcription (Stat)3 and nuclear factor (NF)‑κB signaling pathways determines the radiosensitivity of cancer cells. However, the function of these pathways in radiosensitive vs radioresistant cancer cells remains elusive. The present study demonstrated that adaptive expression of epidermal growth factor (EGF) following exposure to ionizing radiation (IR) may induce radiosensitization of pancreatic cancer (PC) cells through induction of the cyclin D1/P53/poly(ADP‑ribose) polymerase pathway. By contrast, adaptively expressed interleukin (IL)‑6 and insulin‑like growth factor (IGF)‑1 may promote radioresistance of PC cells, likely through activation of the Stat3 and NF‑κB pathways. In addition, cyclin D1 and survivin, which are specifically expressed in the G1/S and G2/M phase of the cell cycle, respectively, are mutually exclusive in radiosensitive and radioresistant PC cells, while Bcl‑2 and Bcl‑xL expression does not differ between radiosensitive and radioresistant PC cells. Therefore, adaptively expressed EGF and IL‑6/IGF‑1 may alter these pathways to promote the radiosensitivity of PC cancers. The findings of the present study highlight potential makers for the evaluation of radiosensitivity and enable the development of effective regimens for cancer radiotherapy.
Bu Y, Shi L, Yu D, et al.CDCA8 is a key mediator of estrogen-stimulated cell proliferation in breast cancer cells.
Gene. 2019; 703:1-6 [PubMed
] Related Publications
Endocrine therapy is effective in the early stage of breast cancer treatment, and most tumor cells will gain the ability to proliferate under residual amounts of estrogen, which will cause the recurrence of the disease. The role of cell division cycle associated 8 (CDCA8) in Estradiol (E2)-stimulated breast cancer cells growth is investigated in this research. CDCA8 showed higher mRNA expression in E2-stimulated MCF7 and T47D cells, and such an increase could also be observed in tumor samples. CDCA8 shRNA inhibited the survival and growth detected by cell number and colony formation, while promoted cell cycle G1 phase arrest determined with flow cytometry, which coordinated with a decrease in E2-induced molecules, namely Cyclin D1 (CCND1), B-Cell CLL/Lymphoma 2 (BCL2), and an increase in apoptosis-related molecules, such as cyclin-dependent kinase inhibitor 1a (P21) and cyclin-dependent kinase inhibitor 1b (P27). Kaplan-Meier plot analysis indicated that higher CDCA8 expression was positively associated with poor prognosis with a probability lower than 0.4 at the five-year interval (p = 0.035). All of these suggest that CDCA8 is a key mediator of estrogen-stimulated breast cancer cell growth and survival, which can be utilized as a novel target in breast cancer treatment.
The dysregulation of Fbxo4-cyclin D1 axis occurs at high frequency in esophageal squamous cell carcinoma (ESCC), where it promotes ESCC development and progression. However, defining a therapeutic vulnerability that results from this dysregulation has remained elusive. Here we demonstrate that Rb and mTORC1 contribute to Gln-addiction upon the dysregulation of the Fbxo4-cyclin D1 axis, which leads to the reprogramming of cellular metabolism. This reprogramming is characterized by reduced energy production and increased sensitivity of ESCC cells to combined treatment with CB-839 (glutaminase 1 inhibitor) plus metformin/phenformin. Of additional importance, this combined treatment has potent efficacy in ESCC cells with acquired resistance to CDK4/6 inhibitors in vitro and in xenograft tumors. Our findings reveal a molecular basis for cancer therapy through targeting glutaminolysis and mitochondrial respiration in ESCC with dysregulated Fbxo4-cyclin D1 axis as well as cancers resistant to CDK4/6 inhibitors.
Steele TM, Talbott GC, Sam A, et al.Obatoclax, a BH3 Mimetic, Enhances Cisplatin-Induced Apoptosis and Decreases the Clonogenicity of Muscle Invasive Bladder Cancer Cells via Mechanisms That Involve the Inhibition of Pro-Survival Molecules as Well as Cell Cycle Regulators.
Int J Mol Sci. 2019; 20(6) [PubMed
] Free Access to Full Article Related Publications
Several studies by our group and others have determined that expression levels of Bcl-2 and/or Bcl-xL, pro-survival molecules which are associated with chemoresistance, are elevated in patients with muscle invasive bladder cancer (MI-BC). The goal of this study was to determine whether combining Obatoclax, a BH3 mimetic which inhibits pro-survival Bcl-2 family members, can improve responses to cisplatin chemotherapy, the standard of care treatment for MI-BC. Three MI-BC cell lines (T24, TCCSuP, 5637) were treated with Obatoclax alone or in combination with cisplatin and/or pre-miR-34a, a molecule which we have previously shown to inhibit MI-BC cell proliferation via decreasing Cdk6 expression. Proliferation, clonogenic, and apoptosis assays confirmed that Obatoclax can decrease cell proliferation and promote apoptosis in a dose-dependent manner. Combination treatment experiments identified Obatoclax + cisplatin as the most effective treatment. Immunoprecipitation and Western analyses indicate that, in addition to being able to inhibit Bcl-2 and Bcl-xL, Obatoclax can also decrease cyclin D1 and Cdk4/6 expression levels. This has not previously been reported. The combined data demonstrate that Obatoclax can inhibit cell proliferation, promote apoptosis, and significantly enhance the effectiveness of cisplatin in MI-BC cells via mechanisms that likely involve the inhibition of both pro-survival molecules and cell cycle regulators.
von Willebrand factor C and EGF domain‑containing protein (URG11), a cell growth regulator, is involved in the progression of a variety of types of cancer, including prostate cancer (Pca). However, the functions of the URG11 gene in Pca cells require in‑depth investigation. The mRNA and protein levels of URG11 were measured by reverse transcription quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis. Cell Counting kit‑8 (CCK‑8), wound‑healing and Transwell assays were used to detect cell viability, migration and invasion, respectively. Apoptosis and cell cycle analyses were performed using flow cytometry. The mRNA and protein expression levels of epithelial (E)‑cadherin, vimentin, α‑smooth muscle actin (α‑SMA), cyclin D1 and MYC proto‑oncogene protein (c‑Myc) were analyzed by RT‑qPCR and western blot analysis. In the present study, the mRNA and protein levels of URG11 were markedly upregulated in Pca cell lines compared with those in the normal prostate epithelial cell line. With functional experiments, the cell viability, migration and invasion of Pca cells were markedly promoted by URG11 overexpression. The cell cycle was effectively induced by URG11 and apoptosis was inhibited by the overexpression of URG11. Concomitantly, the epithelial marker E‑cadherin was downregulated, and the mesenchymal markers vimentin and α‑SMA were upregulated following URG11 overexpression. By contrast, genetic knockout of URG11 elicited the opposite effects. The present study also identified that the downstream effector genes of the Wnt/β‑catenin signal pathway, cyclin D1 and c‑Myc, were increased following the overexpression of endogenous URG11, which are known to regulate cell proliferation. In addition, the Wnt/β‑catenin inhibitor FH535 ameliorated the promotive effects of URG11 on LNCaP cells viability, migration and invasion, and the Wnt/β‑catenin agonist LiCl reversed the inhibitory effects of siURG11 in LNCaP cells on cell viability, migration and invasion. The present study demonstrated that URG11 served an oncogenic role in the development of Pca cells and provided evidence that URG11 has potential as a novel therapeutic target in Pca.
Ni D, Liu J, Hu Y, et al.A1CF-Axin2 signal axis regulates apoptosis and migration in Wilms tumor-derived cells through Wnt/β-catenin pathway.
In Vitro Cell Dev Biol Anim. 2019; 55(4):252-259 [PubMed
] Related Publications
A1CF, a complementary factor of APOBEC-1, is involved in many cellular processes for its mRNA editing role, such as cell proliferation, apoptosis, and migration. Here, we explored the regulatory function of A1CF in Wilms tumor-derived cells. Quantitative real-time PCR was performed to detect the mRNA level of A1CF, Axin2, β-Catenin, CCND1 or NKD1 in A1CF-depleted or A1CF-overexpression G401 cells. Western bolt was used to analyze the expression of A1CF, Axin2, and β-catenin protein. The cell apoptosis and migration ability were determined using flow cytometry assay or wound healing, respectively. Our study demonstrated that overexpression of A1CF, Axin2 was upregulated and knockdown of A1CF decreased Axin2 expression at mRNA and protein levels in G401 cells. Besides, knockdown of A1CF further upregulated β-catenin, the classical regulator of Wnt signal pathway, and increased CCND1 and NKD1, the target genes of Wnt/β-catenin. Furthermore, overexpression of Axin2 partly rescued the expression of β-catenin in A1CF-deficiency stable G401 cells. In Wnt agonist BML-284 treated G401 cells, A1CF was increased like other classical regulator of Wnt signal pathway, such as Axin2 and β-catenin. Meanwhile, knockdown of Axin2 rescued β-catenin expression which was decreased in A1CF overexpression condition with BML-284. Further, overexpression of A1CF reduced cell apoptosis but promoted cell migration, and overexpression of Axin2 got similar results. In A1CF-decreased stable G401 cells, overexpression of Axin2 partly rescued the cell apoptosis and migration. We find that A1CF is a positive regulator of Axin2, a Wnt/β-catenin pathway inhibitor, and A1CF-Axin2 signal axis regulates Wilms tumor-derived cells' apoptosis and migration through Axin2.
BACKGROUND: Use of cyclin D1 (CCND1) gene amplification as a breast cancer biomarker has been hampered by conflicting assessments of the relationship between cyclin D1 protein levels and patient survival. Here, we aimed to clarify its prognostic and treatment predictive potential through comprehensive long-term survival analyses.
METHODS: CCND1 amplification was assessed using SNP arrays from two cohorts of 1965 and 340 patients with matching gene expression array and clinical follow-up data of over 15 years. Kaplan-Meier and multivariable Cox regression analyses were used to determine survival differences between CCND1 amplified vs. non-amplified tumours in clinically relevant patient sets, within PAM50 subtypes and within treatment-specific subgroups. Boxplots and differential gene expression analyses were performed to assess differences between amplified vs. non-amplified tumours within PAM50 subtypes.
RESULTS: When combining both cohorts, worse survival was found for patients with CCND1-amplified tumours in luminal A (HR = 1.68; 95% CI, 1.15-2.46), luminal B (1.37; 1.01-1.86) and ER+/LN-/HER2- (1.66; 1.14-2.41) subgroups. In gene expression analysis, CCND1-amplified luminal A tumours showed increased proliferation (P < 0.001) and decreased progesterone (P = 0.002) levels along with a large overlap in differentially expressed genes when comparing luminal A and B-amplified vs. non-amplified tumours.
CONCLUSIONS: Our results indicate that CCND1 amplification is associated with worse 15-year survival in ER+/LN-/HER2-, luminal A and luminal B patients. Moreover, luminal A CCND1-amplified tumours display gene expression changes consistent with a more aggressive phenotype. These novel findings highlight the potential of CCND1 to identify patients that could benefit from long-term treatment strategies.
Acetyl‑coenzyme A carboxylase 1 (ACC1) serves a major role in fatty acid synthesis. Previous reports have indicated that ACC1 is a promising drug target for treating human diseases, particularly cancers and metabolic diseases; however, the role of ACC1 in liver cancer and normal liver function remains unknown. In the present study, bioinformatics analysis indicated that ACC1 is overexpressed in liver cancer. Kaplan‑Meier survival analysis revealed that the expression levels of ACC1 are highly associated with the prognosis of patients with liver cancer. To determine the role of ACC1 in cancer and normal liver cells, ACC1 expression was downregulated in human hepatoma Hep G2 cells and the rat liver cell line BRL 3A using RNA interference technology, which demonstrated that silencing of ACC1 significantly suppressed the cell viability in the two cell lines. Additionally, ACC1 knockdown decreased the mRNA and protein expression levels of the cell proliferation‑associated genes MYCN, JUN, cyclin D1 (CCND1) and cyclin A2 (CCNA2) in BRL 3A. Furthermore, the number of cells in division phase (G2/M) was significantly reduced in the interference group, as detected by flow cytometry. Thus, ACC1 may bind and activate CCNA2, CCND1, MYCN and JUN to promote BRL 3A proliferation. In summary, the results of present study indicated that overexpression of ACC1 is significantly associated with the survival time of patients with liver cancer, and may provide insight into the association between ACC1 and cell proliferation in BRL 3A cells.
Very young breast cancer patients are more common in Asian countries than Western countries and are thought to have worse prognosis than older patients. The aim of the current study was to identify molecular characteristics of young patients with estrogen receptor (ER)-positive breast cancer by analyzing mutations and copy number variants (CNV), and by applying expression profiling. The whole exome and transcriptome of 47 Korean young breast cancer (KYBR) patients (age <35) were analyzed. Genomic profiles were constructed using mutations, CNV and differential gene expression from sequencing data. Pathway analyses were also performed using gene sets to identify biological processes. Our data were compared with young ER+ breast cancer patients in The Cancer Genome Atlas (TCGA) dataset. TP53, PIK3CA and GATA3 were highly recurrent somatic mutation genes. APOBEC-associated mutation signature was more frequent in KYBR compared with young TCGA patients. Integrative profiling was used to classify our patients into 3 subgroups based on molecular characteristics. Group A showed luminal A-like subtype and IGF1R signal dysregulation. Luminal B patients were classified into groups B and C, which showed chromosomal instability and enrichment for APOBEC3A/B deletions, respectively. Group B was characterized by 11q13 (CCND1) amplification and activation of the ubiquitin-mediated proteolysis pathway. Group C showed 17q12 (ERBB2) amplification and lower ER and progesterone receptor expression. Group C was also distinguished by immune activation and lower epithelial-mesenchyme transition (EMT) degree compared with group B. This study showed that integrative genomic profiling could classify very young patients with breast cancer into molecular subgroups that are potentially linked to different clinical characteristics.
BACKGROUND Gastric cancer is a common gastrointestinal tumor. The incidence and mortality of gastric cancer are very high. Therefore, it is important to study targeted drugs. Recent studies found long chain non-coding RNA (lncRNAs) and microRNAs (miRNAs) were abnormal in gastric cancer. MATERIAL AND METHODS We collected adjacent normal and cancer tissues of gastric cancer patients and measured HOTAIR, miR-454-3p, STAT3, and Cyclin D1 expression and analyzed the correlation with clinical status. We also measured AGS and SGC7901 cells proliferation rate of different groups by MTT assay, and we evaluated AGS and SGC7901 cell apoptosis and cell cycle by flow cytometry. In addition, we assessed the relative proteins expressions by WB assay. Finally, we explored the correlation between miR-454-3p and STAT3 by use of double luciferase reporter. RESULTS lncRNA HOTAIR was negatively correlated with miR-454-3p expression in gastric cancer tissues. lncRNA HOTAIR knockdown suppressed AGS and SGC7901, which are gastric cancer cell lines that promote cell proliferation by increasing cell apoptosis and keeping the cell cycle in G1 phase. In further mechanism research, we found that the STAT3 and Cyclin D1 proteins expressions were suppressed by lncRNA HOTAIR down-regulation in AGS and SGC7901 cells. CONCLUSIONS Our results suggest that lncRNA HOTAIR knockdown stimulates miR-454-3p expression to inhibit gastric cancer growth by depressing STAT3/Cyclin D1 activity.
The correlation of genetic alterations with response to neoadjuvant chemotherapy (NAC) has not been fully revealed. In this study, we enrolled 247 breast cancer patients receiving anthracycline-taxane-based NAC treatment. A next generation sequencing (NGS) panel containing 36 hotspot breast cancer-related genes was used in this study. Two different standards for the extent of pathologic complete response (pCR), ypT0/isypN0 and ypT0/is, were used as indicators for NAC treatment. TP53 mutation (n = 149, 60.3%), PIK3CA mutation (n = 109, 44.1%) and MYC amplification (n = 95, 38.5%) were frequently detected in enrolled cases. TP53 mutation (P = 0.019 for ypT0/isypN0 and P = 0.003 for ypT0/is) and ERBB2 amplification (P < 0.001 for both ypT0/isypN0 and ypT0/is) were related to higher pCR rates. PIK3CA mutation (P = 0.040 for ypT0/isypN0) and CCND2 amplification (P = 0.042 for ypT0/is) showed reduced sensitivity to NAC. Patients with MAPK pathway alteration had low pCR rates (P = 0.043 for ypT0/is). Patients with TP53 mutation (-) PIK3CA mutation (-) ERBB2 amplification (+) CCND1 amplification (-), TP53 mutation (+) PIK3CA mutation (-) ERBB2 amplification (+) CCND1 amplification (-) or TP53 mutation (+) PIK3CA mutation (+) ERBB2 amplification (+) CCND1 amplification (-)had significantly higher pCR rates (P < 0.05 for ypT0/isypN0 and ypT0/is) than wild type genotype tumors. Some cancer genetic alterations as well as pathway alterations were associated with chemosensitivity to NAC treatment. Our study may shed light on the molecular characteristics of breast cancer for prediction of NAC expectations when breast cancer is first diagnosed by biopsy.
Current therapies for most non-infectious diseases are directed at or affect functionality of the human translated genome, barely 2% of all genetic information. By contrast, the therapeutic potential of targeting the transcriptome, ~ 70% of the genome, remains largely unexplored. RNA therapeutics is an emerging field that widens the range of druggable targets and includes elements such as microRNA. Here, we sought to screen for microRNA with tumor-suppressive functions in neuroblastoma, an aggressive pediatric tumor of the sympathetic nervous system that requires the development of new therapies. We found miR-323a-5p and miR-342-5p to be capable of reducing cell proliferation in multiple neuroblastoma cell lines in vitro and in vivo, thereby providing a proof of concept for miRNA-based therapies for neuroblastoma. Furthermore, the combined inhibition of the direct identified targets such as CCND1, CHAF1A, INCENP and BCL-XL could reveal new vulnerabilities of high-risk neuroblastoma.
Cui Y, Su Y, Deng L, Wang WGinsenoside-Rg5 Inhibits Retinoblastoma Proliferation and Induces Apoptosis through Suppressing BCL2 Expression.
Chemotherapy. 2018; 63(5):293-300 [PubMed
] Related Publications
BACKGROUND/AIMS: Although the cure rate for retinoblastoma is high, surviving patients are at risk for developing secondary cancers and require life-long follow-up. It is imperative to discover and develop novel therapeutic agents with better efficiency and fewer adverse effects. Ginsenoside-Rg5 is an active derivate from ginseng and exerts anti-cancer activity in breast cancer cells. However, it is still unclear whether ginsenoside-Rg5 has similar anti-cancer functions in retinoblastoma.
METHODS: Retinoblastoma cells were treated with ginsenoside-Rg5, followed by MTT assay analysis of the cell viability, cell number assay and colony formation assay analyses of cell proliferation, and flow cytometric analysis of apoptosis. Gene mRNA levels and protein levels were determined by quantitative real-time PCR and Western blot, respectively.
RESULTS: Ginsenoside-Rg5 inhibited retinoblastoma cell viability in a dose-dependent and time-dependent manner via preventing cell proliferation and inducing cell apoptosis. BCL2 expression was downregulated by ginsenoside-Rg5 treatment via inactivating the AKT signaling pathway. BCL2 overexpression completely eliminated the inhibitory effect of ginsenoside-Rg5 on cancer cell viability.
CONCLUSION: Ginsenoside-Rg5 inhibits cell proliferation and induces apoptosis in retinoblastoma cells by inactivating the AKT signaling pathway, thereby downregulating BCL2 expression.
Epidemiological studies indicate that long‑term aspirin usage reduces the incidence of colorectal cancer (CRC) and may protect against other non‑CRC associated adenocarcinomas, including oesophageal cancer. A number of hypotheses have been proposed with respect to the molecular action of aspirin and other non‑steroidal anti‑inflammatory drugs in cancer development. The mechanism by which aspirin exhibits toxicity to CRC has been previously investigated by synthesising novel analogues and derivatives of aspirin in an effort to identify functionally significant moieties. Herein, an early effect of aspirin and aspirin‑like analogues against the SW480 CRC cell line was investigated, with a particular focus on critical molecules in the epidermal growth factor (EGF) pathway. The present authors proposed that aspirin, diaspirin and analogues, and diflunisal (a salicylic acid derivative) may rapidly perturb EGF and EGF receptor (EGFR) internalisation. Upon longer incubations, the diaspirins and thioaspirins may inhibit EGFR phosphorylation at Tyr1045 and Tyr1173. It was additionally demonstrated, using a qualitative approach, that EGF internalisation in the SW480 cell line may be directed to endosomes by fumaryldiaspirin using early endosome antigen 1 as an early endosomal marker and that EGF internalisation may also be perturbed in oesophageal cell lines, suggestive of an effect not only restricted to CRC cells. Taken together and in light of our previous findings that the aspirin‑like analogues can affect cyclin D1 expression and nuclear factor‑κB localisation, it was hypothesized that aspirin and aspirin analogues significantly and swiftly perturb the EGFR axis and that the protective activity of aspirin may in part be explained by perturbed EGFR internalisation and activation. These findings may also have implications in understanding the inhibitory effect of aspirin and salicylates on wound healing, given the critical role of EGF in the response to tissue trauma.
Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent. Mechanistically, SMARCA4/2 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-Jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this significant subgroup of NSCLCs.
Cuevas D, Valls J, Gatius S, et al.Targeted sequencing with a customized panel to assess histological typing in endometrial carcinoma.
Virchows Arch. 2019; 474(5):585-598 [PubMed
] Related Publications
The two most frequent types of endometrial cancer (EC) are endometrioid (EEC) and serous carcinomas (SC). Differential diagnosis between them is not always easy. A subset of endometrial cancers shows misleading microscopical features, which cause problems in differential diagnosis, and may be a good scenario for next-generation sequencing. Previous studies have assessed the usefulness of targeted sequencing with panels of generic cancer-associated genes in EC histological typing. Based on the analysis of TCGA (The Cancer Genome Atlas), EEC and SC have different mutational profiles. In this proof of principle study, we have performed targeted sequencing analysis with a customized panel, based on the TCGA mutational profile of EEC and SC, in a series of 24 tumors (16 EEC and 8 SC). Our panel comprised coding and non-coding sequences of the following genes: ABCC9, ARID1A, ARID5B, ATR, BCOR, CCND1, CDH19, CHD4, COL11A1, CSDE1, CSMD3, CTCF, CTNNB1, EP300, ERBB2, FBXW7, FGFR2, FOXA2, KLLN, KMT2B, KRAS, MAP3K4, MKI67, NRAS, PGAP3, PIK3CA, PIK3R1, PPP2R1A, PRPF18, PTEN, RPL22, SCARNA11, SIN3A, SMARCA4, SPOP, TAF1, TP53, TSPYL2, USP36, and WRAP53. Targeted sequencing validation by Sanger sequencing and immunohistochemistry was performed in a group of genes. POLE mutation status was assessed by Sanger sequencing. The most mutated genes were PTEN (93.7%), ARID1A (68.7%), PIK3CA (50%), and KMT2B (43.7%) for EEC, and TP53 (87.5%), PIK3CA (50%), and PPP2R1A (25%) for SC. Our panel allowed correct classification of all tumors in the two categories (EEC, SC). Coexistence of mutations in PTEN, ARID1A, and KMT2B was diagnostic of EEC. On the other hand, absence of PTEN, ARID1A, and KMT2B mutations in the presence of TP53 mutation was diagnostic of SC. This proof of concept study demonstrates the suitability of targeted sequencing with a customized endometrial cancer gene panel as an additional tool for confirming histological typing.
Bollaert E, de Rocca Serra A, Demoulin JBThe HMG box transcription factor HBP1: a cell cycle inhibitor at the crossroads of cancer signaling pathways.
Cell Mol Life Sci. 2019; 76(8):1529-1539 [PubMed
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HMG box protein 1 (HBP1) is a transcription factor and a potent cell cycle inhibitor in normal and cancer cells. HBP1 activates or represses the expression of different cell cycle genes (such as CDKN2A, CDKN1A, and CCND1) through direct DNA binding, cofactor recruitment, chromatin remodeling, or neutralization of other transcription factors. Among these are LEF1, TCF4, and MYC in the WNT/beta-catenin pathway. HBP1 also contributes to oncogenic RAS-induced senescence and terminal cell differentiation. Collectively, these activities suggest a tumor suppressor function. However, HBP1 is not listed among frequently mutated cancer driver genes. Nevertheless, HBP1 expression is lower in several tumor types relative to matched normal tissues. Several micro-RNAs, such as miR-155, miR-17-92, and miR-29a, dampen HBP1 expression in cancer cells of various origins. The phosphatidylinositol-3 kinase (PI3K)/AKT pathway also inhibits HBP1 transcription by preventing FOXO binding to the HBP1 promoter. In addition, AKT directly phosphorylates HBP1, thereby inhibiting its transcriptional activity. Taken together, these findings place HBP1 at the center of a network of micro-RNAs and oncoproteins that control cell proliferation. In this review, we discuss our current understanding of HBP1 function in human physiology and diseases.
Selmin OI, Donovan MG, Skovan B, et al.Arsenic‑induced BRCA1 CpG promoter methylation is associated with the downregulation of ERα and resistance to tamoxifen in MCF7 breast cancer cells and mouse mammary tumor xenografts.
Int J Oncol. 2019; 54(3):869-878 [PubMed
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A significant percentage (~30%) of estrogen receptor‑α (ERα)‑positive tumors become refractory to endocrine therapies; however, the mechanisms responsible for this resistance remain largely unknown. Chronic exposure to arsenic through foods and contaminated water has been linked to an increased incidence of several tumors and long‑term health complications. Preclinical and population studies have indicated that arsenic exposure may interfere with endocrine regulation and increase the risk of breast tumorigenesis. In this study, we examined the effects of sodium arsenite (NaAsIII) exposure in ERα‑positive breast cancer cells in vitro and in mammary tumor xenografts. The results revealed that acute (within 4 days) and long‑term (10 days to 7 weeks) in vitro exposure to environmentally relevant doses reduced breast cancer 1 (BRCA1) and ERα expression associated with the gain of cyclin D1 (CCND1) and folate receptor 1 (FOLR1), and the loss of methylenetetrahydrofolate reductase (MTHFR) expression. Furthermore, long‑term exposure to NaAsIII induced the proliferation and compromised the response of MCF7 cells to tamoxifen (TAM). The in vitro exposure to NaAsIII induced BRCA1 CpG methylation associated with the increased recruitment of DNA methyltransferase 1 (DNMT1) and the loss of RNA polymerase II (PolII) at the BRCA1 gene. Xenografts of NaAsIII‑preconditioned MCF7 cells (MCF7NaAsIII) into the mammary fat pads of nude mice produced a larger tumor volume compared to tumors from control MCF7 cells and were more refractory to TAM in association with the reduced expression of BRCA1 and ERα, CpG hypermethylation of estrogen receptor 1 (ESR1) and BRCA1, and the increased expression of FOLR1. These cumulative data support the hypothesis that exposure to AsIII may contribute to reducing the efficacy of endocrine therapy against ERα‑positive breast tumors by hampering the expression of ERα and BRCA1 via CpG methylation, respectively of ESR1 and BRCA1.
Colorectal cancer (CRC) is the second most common cause of cancer-related death in the world, but early diagnosis ameliorates the survival of CRC. This report aimed to identify molecular biomarker signatures in CRC. We analyzed two microarray datasets (GSE35279 and GSE21815) from the Gene Expression Omnibus (GEO) to identify mutual differentially expressed genes (DEGs). We integrated DEGs with protein⁻protein interaction and transcriptional/post-transcriptional regulatory networks to identify reporter signaling and regulatory molecules; utilized functional overrepresentation and pathway enrichment analyses to elucidate their roles in biological processes and molecular pathways; performed survival analyses to evaluate their prognostic performance; and applied drug repositioning analyses through Connectivity Map (CMap) and geneXpharma tools to hypothesize possible drug candidates targeting reporter molecules. A total of 727 upregulated and 99 downregulated DEGs were detected. The PI3K/Akt signaling, Wnt signaling, extracellular matrix (ECM) interaction, and cell cycle were identified as significantly enriched pathways. Ten hub proteins (ADNP, CCND1, CD44, CDK4, CEBPB, CENPA, CENPH, CENPN, MYC, and RFC2), 10 transcription factors (ETS1, ESR1, GATA1, GATA2, GATA3, AR, YBX1, FOXP3, E2F4, and PRDM14) and two microRNAs (miRNAs) (miR-193b-3p and miR-615-3p) were detected as reporter molecules. The survival analyses through Kaplan⁻Meier curves indicated remarkable performance of reporter molecules in the estimation of survival probability in CRC patients. In addition, several drug candidates including anti-neoplastic and immunomodulating agents were repositioned. This study presents biomarker signatures at protein and RNA levels with prognostic capability in CRC. We think that the molecular signatures and candidate drugs presented in this study might be useful in future studies indenting the development of accurate diagnostic and/or prognostic biomarker screens and efficient therapeutic strategies in CRC.
The farnesoid-X-receptor (FXR) protects against inflammation and cancer of the colon through maintenance of intestinal bile acid (BA) homeostasis. Conversely, higher levels of BA and cyclooxygenase-2 (COX-2) are risk factors for inflammation and cancer of the colon. In the United States,
Parathyroid carcinoma (PC) is a rare endocrine malignancy, accounting for <1% of all cases of sporadic primary hyperparathyroidism (PHPT) and up to 15% in the hereditary hyperparathyroidism-jaw tumor syndrome. Genomic alterations identified in PC are mostly represented by CDC73 gene mutations, codifying for a loss-of-function protein termed parafibromin. Whole exome sequencing identified mutations in other genes, such as mTOR, KMT2D, CDKN2C, THRAP3, PIK3CA, and EZH2 genes, CCND1 gene amplification. The diagnosis of PC is quite difficult due to the lack of reliable clinical diagnostic criteria, and in the majority of cases is made postoperatively at histological examination. The clinical manifestations of PC are primarily due to the excessive secretion of PTH by the tumor rather than spread to local or distant organs. En bloc resection of the parathyroid tumor represents the initial mainstay treatment of patients with PC. Multiple surgical procedures may be required, although surgical morbidity should be taken into account. A 5- and 10-year survival between 77-100 and 49-91%, respectively, has been reported. When the tumor is no more resectable, medical treatment of hypercalcemia has a pivotal role in the management of these patients.
Zhang X, Bai Q, Xu Y, et al.Molecular profiling of the biphasic components of hepatic carcinosarcoma by the use of targeted next-generation sequencing.
Histopathology. 2019; 74(6):944-958 [PubMed
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AIMS: To better understand the tumourogenesis and molecular features of hepatic carcinosarcoma (HCS).
METHODS AND RESULTS: We selected 13 cases of HCS, including the clinicopathological and immunohistochemical features, and analysed the molecular alterations in separately microdissected carcinomatous and sarcomatous components in eight cases by using targeted next-generation sequencing with a panel of 329 cancer-related genes. As a result, transitional areas were observed between the two components of HCS in all cases. Concordance and overlap in genetic alterations were identified in the two histological components of the eight HCS patients, indicating the clonal relatedness of the two tumour components. The most common gene alterations found in both components were TP53 (75%, 6/8) and NF1/2 (38%, 3/8) mutations and VEGFA amplification (25%, 2/8), which may be strongly associated with HCS tumorigenesis. Unique mutations and amplifications found only in one component were also identified. Amplifications involving MET (38%, n = 3/8) and PDGFRA (25%, n = 2/8) were present only in the sarcomatous components, whereas mutation affecting ERBB4 (25%, n = 2/8) and amplifications of CCND1 and FGF3/4/19 (38%, n = 3/8) were present only in the carcinomatous components, indicating their involvement in the clonal evolution of HCS. Furthermore, multiple potential therapeutic targets were identified for HCS.
CONCLUSIONS: Our findings indicate that HCS could have been of monoclonal origin, and that the diverse clonal evolution might be driven by special molecular alterations in each tumour component. Our results also identify multiple therapeutic targets of HCS, which are valuable for the personalised treatment of HCS.
Yang X, Pan Q, Lu Y, et al.MNX1 promotes cell proliferation and activates Wnt/β-catenin signaling in colorectal cancer.
Cell Biol Int. 2019; 43(4):402-408 [PubMed
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Aberrant Wnt/β-catenin signaling is a characteristic feature of colorectal cancer (CRC), therefore, understanding the underlying mechanisms of aberrant Wnt/β-catenin signaling will improve the treatment outcome of CRC. Expression of MNX1 in paired fresh CRC tissues and corresponding adjacent normal tissues were examined by qPCR and Western blotting. The levels of MNX1 in paraffin-embedded CRC specimens were detected by immunohistochemistry (IHC). The role of MNX1 in growth and proliferation of CRC cells was evaluated by MTT and colony formation assay. Luciferase reporter analysis and western blotting were carried out to explore the influence of MNX1 on Wnt/β-catenin signaling. The results showed that expression of MNX1 is markedly upregulated in CRC tissues and positively correlated with level of Ki67, and overexpression of MNX1 significantly promotes the proliferation of CRC cells. Further study showed that ectopic expression of MNX1 activates the Wnt/β-catenin signaling and upregulates the expression of c-Myc and CCND1, the downstream genes of Wnt/β-catenin signaling. Therefore, MNX1 plays an indispensable role in promoting of human CRC progression and may represent a novel therapeutic target for CRC.
Stamatopoulos K, Kosmas C, Belessi C, et al.Molecular analysis of bcl-1/IgH junctional sequences in mantle cell lymphoma: potential mechanism of the t(11;14) chromosomal translocation.
Br J Haematol. 1999; 105(1):190-7 [PubMed
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Mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation that juxtaposes the bcl-1 locus to immunoglobulin (Ig) gene sequences and leads to deregulation of cyclin D1 gene. t(11;14) is thought to result from an error of the recombinase during D-JH Ig gene assembly; however, data on the underlying mechanism and candidate recombination-targeting motifs in the major translocation cluster (MTC) of the bcl-1 gene are lacking. bcl-1/IgH junctional sequences from seven MCL patients were amplified by PCR using primers targeting MTC and JH sequences on chromosomes 11q13 and 14q32, respectively. PCR products were directly sequenced and junctional sequences were searched for homology to known germline D genes. bcl-t MTC breakpoints were searched for the presence of possible recombination target motifs; heptamers, nonamers, binding sequence of the bp45 nuclease, x-like sequences and D gene segments. bcl-1/JH junctions were found to bear homology to D gene segments (DLR3, DM and DIR5) in 3/7 MCL samples. A computer-based search in previously published and/or submitted to GenBank bcl-1/JH junctional sequences identified homology to D genes in 1/4 MCL tumour samples and 1/4 MCl cell lines; DXP4 or D23/7 and DHQ52 or D22/21 or DXP5, respectively. The MTC locus contained motifs with homology to bp45 nuclease binding sequence, x-like sequences, heptamers/nonamers, D-like DIR genes and non-homologous recombination short (6 bp) DNA sequences. The above data indicate that the t(11;14) translocation in MCL may also occur at a more mature stage of B-cell ontogeny than previously thought, i.e. during VH-to-DJH rearrangement. Various known recombination motifs within MTC may contribute to an illegitimate recombination event between bcl-1 and DJH.
Espinet B, Solé F, Woessner S, et al.Translocation (11;14)(q13;q32) and preferential involvement of chromosomes 1, 2, 9, 13, and 17 in mantle cell lymphoma.
Cancer Genet Cytogenet. 1999; 111(1):92-8 [PubMed
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We have studied 13 cases of histologically confirmed mantle cell lymphomas (MCL) combining cytological-immunological features with conventional cytogenetics and in situ hybridization (ISH) techniques. Peripheral blood smears and lymph node biopsies expressed the typical mantle zone pattern with alpha B-cell phenotype. Most of the cases (11 of 13) had lymphomatous cells in the peripheral blood. Chromosome analysis was carried out on lymphoid cells from peripheral blood and/or lymph node biopsies. Phytohemagglutinin (PHA) and phorbol 12-myristate 13 acetate (TPA) were used as mitogens. Biotin-labeled libraries of whole chromosomes implicated in complex karyotypes were used to improve their interpretation. Clonal chromosome abnormalities were found in 10 of 13 patients (77%); 7 of these had a complex abnormality. The most frequent recurrent structural abnormalities were: t(11;14)(q13;q32), involvement of chromosome 1 (der, del, dup), chromosome 2 (del, der), chromosome 9 (der, -9), chromosome 13 (add, t[13q]), and chromosome 17 (add, der, t[17q]). The most frequent numerical abnormalities were monosomy 21 and loss of the Y chromosome.