Coactivator-associated arginine methyltransferase 1 (CARM1), a coactivator for various cancer-relevant transcription factors, is overexpressed in breast cancer. To elucidate the functions of CARM1 in ...tumorigenesis, we knocked out CARM1 from several breast cancer cell lines using Zinc-Finger Nuclease technology, which resulted in drastic phenotypic and biochemical changes. The CARM1 KO cell lines enabled identification of CARM1 substrates, notably the SWI/SNF core subunit BAF155. Methylation of BAF155 at R1064 was found to be an independent prognostic biomarker for cancer recurrence and to regulate breast cancer cell migration and metastasis. Furthermore, CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation.
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•Knockout of CARM1 Using ZFN in Breast Cancer Cells•Identification of BAF155 as a Novel CARM1 Substrate•Methylation of BAF155 Promotes Tumor Growth and Metastasis•Methylated BAF155 Gains Unique Chromatin Association
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To retrospectively investigate the value of computerized three-dimensional texture analysis for differentiation of preinvasive lesions from invasive pulmonary adenocarcinomas (IPAs) that manifest as ...part-solid ground-glass nodules (GGNs).
The institutional review board approved this retrospective study with a waiver of patients' informed consent. The study consisted of 86 patients with 86 pathologic analysis-confirmed part-solid GGNs (mean size, 16 mm ± 5.4 standard deviation) who had undergone computed tomographic (CT) imaging between January 2005 and October 2011. Each part-solid GGN was manually segmented and its computerized texture features were quantitatively extracted by using an in-house software program. Multivariate logistic regression analysis was performed to investigate the differentiating factors of preinvasive lesions from IPAs. Three-layered artificial neural networks (ANNs) with a back-propagation algorithm and receiver operating characteristic curve analysis were used to build a discriminating model with texture features and to evaluate its discriminating performance.
Pathologic analysis confirmed 58 IPAs (seven minimally invasive adenocarcinomas and 51 invasive adenocarcinomas) and 28 preinvasive lesions (four atypical adenomatous hyperplasias and 24 adenocarcinomas in situ). IPAs and preinvasive lesions exhibited significant differences in various histograms and volumetric parameters (P < .05). Multivariate analysis revealed that smaller mass (adjusted odds ratio, 0.092) and higher kurtosis (adjusted odds ratio, 3.319) are significant differentiators of preinvasive lesions from IPAs (P < .05). With mean attenuation, standard deviation of attenuation, mass, kurtosis, and entropy, the ANNs model showed excellent accuracy in differentiation of preinvasive lesions from IPAs (area under the curve, 0.981).
In part-solid GGNs, higher kurtosis and smaller mass are significant differentiators of preinvasive lesions from IPAs, and preinvasive lesions can be accurately differentiated from IPAs by using computerized texture analysis. Online supplemental material is available for this article.
Hepatocellular carcinoma (HCC) is the one of the most common malignancies worldwide and its prognosis is extremely poor. Tripartite motif (TRIM) proteins play crucial roles in cancer cell biology but ...the function of tripartite motif 26 (TRIM26) has not been investigated. We demonstrated that low expression level of TRIM26 in tumor samples was significantly correlated with worse prognosis in HCC patients. We also demonstrated its expression level was associated with several clinicopathologic features such as AFP level and T stage of HCC patients. Furthermore, we validated that TRIM26 was significantly downregulated in HCC tissue compared with normal liver tissue. To further clarify the functional role of TRIM26 in HCC, We confirmed that TRIM26 silencing can promote cancer cell proliferation, colony forming, migration and invasion in vitro with HCC cell lines HepG2 and Bel-7402. Then we utilized bioinformatic tool to predict gene influenced by TRIM26, showing TRIM26 could modulate gene sets about cancer cell metabolism. In conclusion, we proved that TRIM26 is a novel tumor suppressor modulating multiple metabolism-related pathways in HCC. To our best knowledge, this is the first study to investigate the function of TRIM26 in cancer biology. Our findings provide useful insight into the mechanism of HCC origin and progression. Moreover, TRIM26 may represent a novel therapeutic target for HCC.
•TRIM26 is down-regulated in liver cancer samples and functions as a novel tumor suppressor.•Down-regulation of TRIM26 is associated with worse prognosis of hepatocellular carcinoma (HCC).•Knockdown of TRIM26 promotes the proliferation and metastasis of HCC cells.•TRIM26 may function in abnormal metabolic progress of HCC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Circular RNA (circRNA) play important roles in the pathological processes of many diseases. By analyzing the results of the GSE100186 chip, we found that the expression of circRNA ZNF609 ...(circ‐ZNF609) was significantly increased in renal cell carcinoma. Recently, there are studies showing that circ‐ZNF609 can regulate cell proliferation and invasion ability of various cells. In this study, we investigated whether circ‐ZNF609 may affect cell invasion and proliferation in renal carcinoma. Quantitative reverse transcription polymerase chain reaction was performed to detect the expression of circ‐ZNF609 in renal carcinoma cell lines and renal epithelial cells. The direct interaction between microRNA‐138‐5p (miR‐138‐5p) and forkhead box P4 (FOXP4) or circ‐ZNF609 was confirmed by luciferase reporter assay and RNA immunoprecipitation assay. We use Cell Counting Kit‐8, 5‐ethynyl‐2′‐deoxyuridine, and Matrigel assays to assess the effect of miR‐138‐5p or circ‐ZNF609 on cell proliferation or invasion ability. And we found that circ‐ZNF609 is significantly increased in renal carcinoma cell lines. In addition, the high expression of circ‐ZNF609 promotes cell proliferation and invasion ability. In short, our current study reveals the role of the circ‐ZNF609/miR‐138‐5p/FOXP4 regulatory network in renal carcinoma and provides a new perspective for the pathogenesis of renal carcinoma.
Our research indicates that circRNA ZNF609 (circ‐ZNF609) functions as a competitive endogenous RNA to regulate forkhead box P4 expression by sponging microRNA‐138‐5p has great significance in the pathogenesis of renal carcinoma. Therefore, further study of circRNA may have clinical implications for future diagnosis and treatment of renal carcinoma and other diseases.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To better define malignant pleural mesothelioma (MPM) heterogeneity and identify molecular subtypes of MPM, we focus on the tumor suppressor gene
, a member of the Hippo signaling pathway, which ...plays a key role in mesothelial carcinogenesis.
Sixty-one MPM primary cultures established in our laboratory were screened for mutations in
Gene inactivation was modeled using siRNAs. Gene and protein expressions were analyzed by quantitative RT-PCR, Western blot analysis, and reverse phase protein array. Cell proliferation, viability, apoptosis, mobility, and invasion were determined after siRNA knockdown or YAP (verteporfin), mTOR (rapamycin), and mTOR/PI3K/AKT (PF-04691502) inhibitor treatment.
The
gene was altered in 11% of MPM by point mutations and large exon deletions. Genetic data coupled with transcriptomic data allowed the identification of a new MPM molecular subgroup, C2
, characterized by a co-occurring mutation in the
and
genes in the same MPM. MPM patients of this subgroup presented a poor prognosis. Coinactivation of
and
leads to loss of cell contact inhibition between MPM cells. Hippo signaling pathway activity, mTOR expression, and phosphorylation were altered in the C2
MPM subgroup. MPMs of this new subgroup show higher sensitivity to PF-04691502 inhibitor. The
gene was identified as a potential biomarker of the C2
MPM subgroup and PF-04691502 sensitivity.
We identified a new MPM molecular subgroup that shares common genetic and transcriptomic characteristics. Our results made it possible to highlight a greater sensitivity to an anticancer compound for this MPM subgroup and to identify a specific potential biomarker.
.
Summary Background Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin ...versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. Methods We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash—a class effect of EGFR antibodies—that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov , number NCT00981058. Findings Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months 95% CI 10·4–12·6) vs 9·9 months 8·9–11·1; stratified hazard ratio 0·84 95% CI 0·74–0·96; p=0·01). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 72% of 538 patients) than in the gemcitabine and cisplatin group (333 62% of 541), as was the incidence of serious adverse events (257 48% of 538 patients vs 203 38% of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3–4 hypomagnesaemia (47 9% of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six 1% of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 4% vs one <1%). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations. Interpretation Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. Funding Eli Lilly and Company.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Long non‐coding RNA (lncRNA) have been the focus of increasing attention due to the role they play in many diseases, including osteosarcoma. The function of taurine upregulated gene 1 (TUG1) and its ...mechanism in osteosarcoma remain unclear. In our research, we found that TUG1 was elevated and correlated with a poor prognosis in osteosarcoma patients. In addition, the following functional experiment showed that decreased TUG1 could remarkably inhibit osteosarcoma cell migration and invasion, indicating that TUG1 functioned as an oncogene in osteosarcoma. Moreover, we revealed that TUG1 and Rho‐associated coiled‐coil‐containing protein kinase 1 (ROCK1), a metastasis‐related gene targeted by microRNA‐335‐5p (miR‐335‐5p), had the same miR‐335‐5p combining site. The subsequent luciferase assay verified TUG1 was a target of miR‐335‐5p. Furthermore, the results of a real‐time quantitative PCR showed that TUG1 and miR‐335‐5p could affect each other's expression. respectively. Finally, we affirmed that TUG1 affected ROCK1 expression and ROCK1‐mediated migration/invasion by working as a competitive endogenous RNA (ceRNA) via miR‐335‐5p. In summary, the findings of this study, based on ceRNA theory, combining the research foundation of miR‐335‐5p and ROCK1, and taking TUG1 as a new study point, provide new insight into molecular‐level reversing migration and invasion of osteosarcoma.
TUG1 was a target of miR‐335‐5p in osteosarcoma tissues and cell lines. TUG1 could increase ROCK1 expresion and promote ROCK1 mediated migration/invasion by working as a ceRNA of miR‐335‐5p.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Despite being the hallmark of cancer that is responsible for the highest number of deaths, very little is known about the biology of metastasis. Metastatic disease typically manifests after a ...protracted period of undetectable disease following surgery or systemic therapy, owing to relapse or recurrence. In the case of breast cancer, metastatic relapse can occur months to decades after initial diagnosis and treatment. In this review, we provide an overview of the known key factors that influence metastatic recurrence, with the goal of highlighting the critical unanswered questions that still need to be addressed to make a difference in the mortality of breast cancer patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Chemokines are a family of soluble cytokines that act as chemoattractants to guide the migration of cells, in particular of immune cells. However, chemokines are also involved in cell proliferation, ...differentiation, and survival. Chemokines are associated with a variety of human diseases including chronic inflammation, immune dysfunction, cancer, and metastasis. This review discusses the expression of CC and CXC chemokines in the tumor microenvironment and their supportive and inhibitory roles in tumor progression, angiogenesis, metastasis, and tumor immunity. We also specially focus on the diverse roles of CXC chemokines (CXCL9-11, CXCL4 and its variant CXCL4L1) and their two chemokine receptor CXCR3 isoforms, CXCR3-A and CXCR3-B. These two distinct isoforms have divergent roles in tumors, either promoting (CXCR3-A) or inhibiting (CXCR3-B) tumor progression. Their effects are mediated not only directly in tumor cells but also indirectly via the regulation of angiogenesis and tumor immunity. A full comprehension of their mechanisms of action is critical to further validate these chemokines and their receptors as biomarkers or therapeutic targets in cancer.
Colorectal cancers with deficient DNA mismatch repair (dMMR) are presumed to uniformly have dense lymphocytic infiltration that underlies their favorable prognosis and is critical to their ...responsiveness to immunotherapy, as compared with MMR-proficient (pMMR) tumors. We examined T-cell densities and their potential heterogeneity in a large cohort of dMMR tumors.
CD3
and CD8
T-cell densities were quantified at the invasive margin (IM) and tumor core (CT) in 561 stage III colon cancers (dMMR,
= 278; pMMR,
= 283) from a phase III adjuvant trial (N0147). Their association with overall survival (OS) was determined using multivariable Cox analysis.
Although CD3
and CD8
T-cell densities in the tumor microenvironment were higher in dMMR versus pMMR tumors overall, intertumoral heterogeneity in densities between tumors was significantly higher by 30% to 88% among dMMR versus pMMR cancers (
< 0.0001 for all four T-cell subtypes CD3
IM, CD3
CT, CD8
IM, CD8
CT). A substantial proportion of dMMR tumors (26% to 35% depending on the T-cell subtype) exhibited T-cell densities as low as that in the bottom half of pMMR tumors. All four T-cell subtypes were prognostic in dMMR with CD3
IM being the most strongly prognostic. Low (vs. high) CD3
IM was independently associated with poorer OS among dMMR (HR, 4.76; 95% confidence interval, 1.43-15.87;
= 0.0019) and pMMR tumors (
= 0.0103).
Tumor-infiltrating T-cell densities exhibited greater intertumoral heterogeneity among dMMR than pMMR colon cancers, with CD3
IM providing robust stratification of both dMMR and pMMR tumors for prognosis. Potentially, lower T-cell densities among dMMR tumors may contribute to immunotherapy resistance.
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