Dualistic classification of high grade serous ovarian carcinoma has its root in spatial heterogeneity.

INTRODUCTION: Widespread intra-peritoneal metastases is a main feature of high grade serous ovarian carcinoma (HGSOC). Recently, the extent of tumour heterogeneity was used to evaluate the cancer genomes among multi-regions in HGSOC. However, there is no consensus on the effect of tumour heterogeneity on the evolution of the tumour metastasis process in HGSOC. OBJECTIVES: We performed whole-exome sequencing in multiple regions of matched primary and metastatic HGSOC specimens to reveal the genetic mechanisms of ovarian tumourigenesis and malignant progression. METHODS: 63 samples (including ovarian carcinoma, omentum metastasis, and normal tissues) were used. We analyzed the genomic heterogeneity, traced the subclone dissemination and establishment history and compared the different genetic characters of cancer evolutionary models in HGSOC. RESULTS: We found that HGSOC had substantial intra-tumour heterogeneity (median 54.2, range 0 âˆ¼ 106.7), high inter-patient heterogeneity (P < 0.001), but relatively limited intra-patient heterogeneity (P = 0.949). Two COSMIC mutational signatures were identified in HGSOCs: signature 3 was related to homologous recombination, and signature 1 was associated with aging. Two scenarios were identified by phylogenetic reconstruction in our study: 3 cases (33.3 %) showed star topology, and the other 6 cases (66.7 %) displayed tree topology. Compared with star topology group, more driver events were identified in tree topology group (P < 0.001), and occurred more frequently in early stage than in late stage of clonal evolution (P < 0.001). Moreover, compared with the star topology group, the tree topology group showed higher rate of intra-tumour heterogeneity (P = 0.045). CONCLUSION: A dualistic classification model was proposed for the classification of HGSOC based on spatial heterogeneity, which may contribute to better managing patients and providing individual treatment for HGSOC patients.

Anaplastic carcinoma showing rhabdoid features combined with ovarian mucinous borderline cystadenoma: a case report and literature review.

Anaplastic carcinoma in an ovarian tumor (ACOT) is rare. There have been a few controversial cases illustrating the clinical characteristics and prognostic factors of ACOT, which are not well known. A 60-year-old Chinese woman presented with a large pelvic tumor. A transvaginal ultrasound examination showed a large single ovarian cystic tumor with mural nodules and ascites. A gross ovarian mass with a size of approximately 20 × 10×15 cm3 was found. The content of the ovarian cyst was light yellow and chocolate-like, and a large grayish mural nodule of approximately 10 cm was found on the cyst wall. Histological diagnosis of ovarian mucinous borderline cystadenoma with a mural nodule of anaplastic carcinoma showing rhabdoid features and International Federation of Gynecology and Obstetrics (FIGO) stage IIIa was made. Fifteen months after surgery, the patient had received six courses of paclitaxel and carboplatin. She is still alive without any recurrence of the tumor. Findings from the present case suggest that patients with ACOT and FIGO stage IIIa would benefit from surgery and chemotherapy of paclitaxel and carboplatin. We also review the clinical features and survival rate of patients with ACOT using the Surveillance, Epidemiology, and End Result database, and summarize previously reported treatments.

MYBL2 disrupts the Hippo-YAP pathway and confers castration resistance and metastatic potential in prostate cancer.

Rationale: Resistance to androgen-deprivation therapy (ADT) associated with metastatic progression remains a challenging clinical task in prostate cancer (PCa) treatment. Current targeted therapies for castration-resistant prostate cancer (CRPC) are not durable. The exact molecular mechanisms mediating resistance to castration therapy that lead to CRPC progression remain obscure. Methods: The expression of MYB proto-oncogene like 2 (MYBL2) was evaluated in PCa samples. The effect of MYBL2 on the response to ADT was determined by in vitro and in vivo experiments. The survival of patients with PCa was analyzed using clinical specimens (n = 132) and data from The Cancer Genome Atlas (n = 450). The mechanistic model of MYBL2 in regulating gene expression was further detected by subcellular fractionation, western blotting, quantitative real-time PCR, chromatin immunoprecipitation, and luciferase reporter assays. Results: MYBL2 expression was significantly upregulated in CRPC tissues and cell lines. Overexpression of MYBL2 could facilitate castration-resistant growth and metastatic capacity in androgen-dependent PCa cells by promoting YAP1 transcriptional activity via modulating the activity of the Rho GTPases RhoA and LATS1 kinase. Importantly, targeting MYBL2, or treatment with either the YAP/TAZ inhibitor Verteporfin or the RhoA inhibitor Simvastatin, reversed the resistance to ADT and blocked bone metastasis in CRPC cells. Finally, high MYBL2 levels were positively associated with TNM stage, total PSA level, and Gleason score and predicted a higher risk of metastatic relapse and poor prognosis in patients with PCa. Conclusions: Our results reveal a novel molecular mechanism conferring resistance to ADT and provide a strong rationale for potential therapeutic strategies against CRPC.

Single-cell transcriptomic landscape reveals the differences in cell differentiation and immune microenvironment of papillary thyroid carcinoma between genders.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the main pathological type of thyroid carcinoma (TC). Gender is a prominent background parameter for patients with PTC. Here, we aimed to delineate the differences in cell clusters and immune microenvironment in relation to gender in PTC. METHODS: We generated 6720, 14,666, and 33,373 single-cell transcriptomes that were pooled from the tissues of four male patients with PTC, seven female patients with PTC, and three patients with nodular goiter, respectively. We performed single-cell RNA-sequencing (scRNA-seq) based on BD Rhapsody and characterized the first single-cell transcriptomic landscape of PTC involving gender. The differential cell clusters and their gene profiles were identified and analyzed via a multi-resolution network in male and female patients. The interactions of fibroblasts and endothelial cells with malignant epithelial cells and the difference in the immune infiltration of B and T lymphocytes according to gender were assessed. RESULTS: Malignant epithelial cells were divided into two distinct subsets in male and female patients with PTC. Moreover, significant differences involving inferred copy-number variations (CNVs), gene profiles, and cell differentiation were detected between male and female patients. Regarding the interactions of fibroblasts and endothelial cells with malignant epithelial cells, members of the human leukocyte antigen (HLA) family and their receptors were considered as typical in female patients with PTC, while transforming growth factor beta 1 (TGFB1) and its receptors were typical of male patients with PTC. The characteristics of B cells, including cell clusters, cell differentiation, and dominant gene sets, were significantly different between genders. CONCLUSIONS: Our data revealed the detailed differences in cell clusters and immune microenvironment in PTC according to gender at the single-cell level, which provided new insights into the understanding of the impact of gender on PTC.

Deletion of Wild-type p53 Facilitates Bone Metastatic Function by Blocking the AIP4 Mediated Ligand-Induced Degradation of CXCR4.

Background: Management of patients with prostate cancer and bone metastatic disease remains a major clinical challenge. Loss or mutation of p53 has been identified to be involved in the tumor progression and metastasis. Nevertheless, direct evidence of a specific role for wild-type p53 (wt-p53) in bone metastasis and the mechanism by which this function is mediated in prostate cancer remain obscure. Methods: The expression and protein levels of wt-53, AIP4, and CXCR4 in prostate cancer cells and clinical specimens were assessed by real-time PCR, immunohistochemistry and western blot analysis. The role of wt-p53 in suppressing aggressive and metastatic tumor phenotypes was assessed using in vitro transwell chemotaxis, wound healing, and competitive colocalization assays. Furthermore, whether p53 deletion facilitates prostate cancer bone-metastatic capacity was explored using an in vivo bone-metastatic model. The mechanistic model of wt-p53 in regulating gene expression was further explored by a luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. Results: Our findings revealed that wt-p53 suppressed the prostate cancer cell migration rate, chemotaxis and attachment toward the osteoblasts in vitro. The bone-metastatic model showed that deletion of wt-p53 remarkably increased prostate cancer bone-metastatic capacity in vivo. Mechanistically, wt-p53 could induce the ligand-induced degradation of the chemokine receptor CXCR4 by transcriptionally upregulating the expression of ubiquitin ligase AIP4. Treatment with the CXCR4 inhibitor AMD3100 or transduction of the AIP4 plasmid abrogated the pro-bone metastasis effects of TP53 deletion. Conclusion: Wt-p53 suppresses the metastasis of prostate cancer cells to bones by regulating the CXCR4/CXCL12 activity in the tumor cells/bone marrow microenvironment interactions. Our findings suggest that targeting the wt-p53/AIP4/CXCR4 axis might be a promising therapeutic strategy to manage prostate cancer bone metastasis.

SMAD3/SP1 complex-mediated constitutive active loop between lncRNA PCAT7 and TGF-ß signaling promotes prostate cancer bone metastasis.

Bone metastasis is associated with cancer-related death in patients with prostate cancer (PCa). Long noncoding RNAs (lncRNAs) play critical roles in tumor progression of PCa. Nevertheless, the biological function of lncRNAs in PCa bone metastasis remains unclear. PCAT7 was identified as a bone metastasis-related lncRNA via analyzing TCGA dataset. Meanwhile, PCAT7 was found to be elevated in primary PCa tissues with bone metastasis and associated with bone metastasis status and poor prognosis of patients with PCa. Functionally, our results reveal that PCAT7 overexpression promotes PCa bone metastasis in vivo, as well as migration, invasion, and EMT of PCa cells in vitro; on the contrary, PCAT7 knockdown has an inverse effect. Mechanistically, PCAT7 activates TGF-ß/SMAD signaling by upregulating TGFBR1 expression via sponging miR-324-5p. In turn, TGF-ß signaling forms a positive feedback loop with PCAT7 via SMAD3/SP1 complex-induced PCAT7 upregulation. Finally, the clinical positive correlation between PCAT7 and TGFBR1 and TGF-ß signaling activity, and the negative association with miR-324-5p are further demonstrated in PCa tissues and clinical primary PCa cells. This study reveals a novel mechanism that is responsible for the constitutive activation of TGF-ß signaling in PCa bone metastasis, implying that PCAT7 can act as a potential therapeutic target against bone metastasis of PCa via disrupting the constitutive active loop between PCAT7 and TGF-ß signaling.

Copy number gain of ZEB1 mediates a double-negative feedback loop with miR-33a-5p that regulates EMT and bone metastasis of prostate cancer dependent on TGF-ß signaling.

Background: The reciprocal repressive loop between ZEB1 and miRNAs has been extensively reported to play an important role in tumor progression and metastasis of various human tumor types. The aim of this study was to elucidate the role and the underlying mechanism of the double-negative feedback loop between ZEB1and miR-33a-5p in bone metastasis of prostate cancer (PCa). Methods: miR-33a-5p expression was examined in 40 bone metastatic and 165 non-bone metastatic PCa tissues by real-time PCR. Statistical analysis was performed to evaluate the clinical correlation between miR-33a-5p expression and clinicopathological characteristics, and overall and bone metastasis-free survival in PCa patients. The biological roles of miR-33a-5p in bone metastasis of PCa were investigated both by EMT and the Transwell assay in vitro, and by a mouse model of left cardiac ventricle inoculation in vivo. siRNA library, real-time PCR and chromatin immunoprecipitation (ChIP) were used to identify the underlying mechanism responsible for the decreased expression of miR-33a-5p in PCa. Bioinformatics analysis, Western blotting and luciferase reporter analysis were employed to examine the relationship between miR-33a-5p and its potential targets. Clinical correlation of miR-33a-5p with its targets was examined in human PCa tissues and primary PCa cells. Results: miR-33a-5p expression was downregulated in PCa tissues with bone metastasis and bone-derived cells, and low expression of miR-33a-5p strongly and positively correlated with advanced clinicopathological characteristics, and shorter overall and bone metastasis-free survival in PCa patients. Upregulating miR-33a-5p inhibited, while silencing miR-33a-5p promoted EMT, invasion and migration of PCa cells. Importantly, upregulating miR-33a-5p significantly repressed bone metastasis of PC-3 cells in vivo. Our results further revealed that recurrent ZEB1 upregulation induced by copy number gains transcriptionally inhibited miR-33a-5p expression, contributing to the reduced expression of miR-33a-5p in bone metastatic PCa tissues. In turn, miR-33a-5p formed a double negative feedback loop with ZEB1 in target-independent manner, which was dependent on TGF-ß signaling. Finally, the clinical negative correlations of miR-33a-5p with ZEB1 expression and TGF-ß signaling activity were demonstrated in PCa tissues and primary PCa cells. Conclusion: Our findings elucidated that copy number gains of ZEB1-triggered a TGF-ß signaling-dependent miR-33a-5p-mediated negative feedback loop was highly relevant to the bone metastasis of PCa.

Development and Validation of a Novel Signature to Predict Overall Survival in "Driver Gene-negative" Lung Adenocarcinoma (LUAD): Results of a Multicenter Study.

PURPOSE: Examining the role of developmental signaling pathways in "driver gene-negative" lung adenocarcinoma (patients with lung adenocarcinoma negative for EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1 were identified as "driver gene-negative") may shed light on the clinical research and treatment for this lung adenocarcinoma subgroup. We aimed to investigate whether developmental signaling pathways activation can stratify the risk of "driver gene-negative" lung adenocarcinoma. EXPERIMENTAL DESIGN: In the discovery phase, we profiled the mRNA expression of each candidate gene using genome-wide microarrays in 52 paired lung adenocarcinoma and adjacent normal tissues. In the training phase, tissue microarrays and LASSO Cox regression analysis were applied to further screen candidate molecules in 189 patients, and we developed a predictive signature. In the validation phase, one internal cohort and two external cohorts were used to validate our novel prognostic signature. RESULTS: Kyoto Encyclopedia of Genes and Genomes pathway analysis based on whole-genome microarrays indicated that the Wnt/ß-catenin pathway was activated in "driver gene-negative" lung adenocarcinoma. Furthermore, the Wnt/ß-catenin pathway-based gene expression profiles revealed 39 transcripts differentially expressed. Finally, a Wnt/ß-catenin pathway-based CSDW signature comprising 4 genes (CTNNB1 or ß-catenin, SOX9, DVL3, and Wnt2b) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival [HR, 10.42; 6.46-16.79; P < 0.001) than patients with low-risk scores. CONCLUSIONS: The CSDW signature is a reliable prognostic tool and may represent genes that are potential drug targets for "driver gene-negative" lung adenocarcinoma.

Wnt5a induces and maintains prostate cancer cells dormancy in bone.

In a substantial fraction of prostate cancer (PCa) patients, bone metastasis appears after years or even decades of latency. Canonical Wnt/ß-catenin signaling has been proposed to be implicated in dormancy of cancer cells. However, how these tumor cells are kept dormant and recur under control of Wnt/ß-catenin signaling derived from bone microenvironment remains unknown. Here, we report that Wnt5a from osteoblastic niche induces dormancy of PCa cells in a reversible manner in vitro and in vivo via inducing Siah E3 Ubiquitin Protein Ligase 2 (SIAH2) expression, which represses Wnt/ß-catenin signaling. Furthermore, this effect of Wnt5a-induced dormancy of PCa cells depends on receptor tyrosine kinase-like orphan receptor 2 (ROR2), and a negative correlation of ROR2 expression with bone metastasis-free survival is observed in PCa patients. Therefore, these results demonstrate that Wnt5a/ROR2/SIAH2 signaling axis plays a crucial role in inducing and maintaining PCa cells dormancy in bone, suggesting a potential therapeutic utility of Wnt5a via inducing dormancy of PCa cells in bone.

HOXC10 promotes gastric cancer cell invasion and migration via regulation of the NF-κB pathway.

Homeobox gene C10 (HOXC10), known to regulate cell differentiation and proliferation, is upregulated in gastric cancer (GC). The mechanism underlying HOXC10 involvement in GC metastasis is unclear. Herein, we found that HOXC10 is overexpressed in GC relative to normal controls. In the 73 GC patients tissue microarrays (TMA) tested, HOXC10 expression was closely related with tumor-node-metastasis (TNM) stage, lymph node metastasis, and distant metastasis. HOXC10 overexpression tended to associate with low 5-year cumulative survival. Cox regression analysis identified HOXC10 as an independent prognostic factor for poor patient survival. HOXC10 promoted GC cell invasion and migration, regulated the expression of activated ATM and markers of NF-κB signaling. HOXC10 may promote invasion and migration of GC by regulating ATM/NF-κB signaling pathway. HOXC10 should be explored as a clinical marker of GC prognosis.

Primary pulmonary synovial sarcoma: a case report.

Primary pulmonary synovial sarcoma (PPSS) is a relatively rare mesenchymal tumor accounting for 0.5% of all primary lung malignancy with a highly progressive potential. We describe a case of a 52-year-old man whose chest CT-imaging revealed a heterogeneous mass (8.5 × 7.7 × 6.5 cm), with multiple nearly-circular nodules in bilateral pulmonary tissues. EBUS-TBNA and pathological H&E and immunohistochemical examination were performed subsequently, and sarcoma was suspected. Then molecular detection was used and PPSS was confirmed by the detection of the expression of SYT gene (positive) and EWSR1 gene (negative) in situ hybridization. This report shows that EBUS-TBNA combined with in situ hybridization could serve as a helpful diagnostic tool.

The TGF-ß signalling negative regulator PICK1 represses prostate cancer metastasis to bone.

Backgroud:Constitutive activation of TGF-ß signalling is a well-recognised mechanism in bone metastasis of prostate cancer (PCa). Protein Interacting with PRKCA 1 (PICK1) is a critical negative regulator of the TGF-ß pathway. However, the clinical significance and biological role of PICK1 in PCa bone metastasis remain obscure. METHODS: PICK1 expression is evaluated by immunohistochemistry (IHC) in 198 PCa patients. Statistical analysis is performed to explore correlation between PICK1 expression and clinicopathological features in PCa patients. The biological role of PICK1 is examined in PC-3 and C4-2B cells in vitro and a mouse intracardial model in vivo. RESULTS: PICK1 expression is decreased in PCa tissues with bone metastasis and bone-derived cells and downregulation of PICK1 positively correlates with serum PSA level, Gleason grade and bone metastasis status in PCa patients. Overexpression of PICK1 suppresses PCa cell invasion and migration in vitro and bone metastasis in vivo. Our results further indicate downregulation of PICK1 is caused by miR-210-3p overexpression in PCa tissues with bone metastasis. Clinical negative correlation of PICK1 with miR-210-3p is confirmed in PCa tissues. CONCLUSIONS: Our findings uncover a novel functionally and clinically relevant epigenetic regulatory mechanism for constitutive activation of TGF-ß signalling in bone metastasis of PCa.

FZD8, a target of p53, promotes bone metastasis in prostate cancer by activating canonical Wnt/ß-catenin signaling.

Prostate cancer (PCa) is the second most frequently diagnosed cancer among men and exhibits a high propensity to metastasize to bone. Currently, bone metastasis remains incurable, and therapies are limited. A better understanding of the molecular mechanisms involved in PCa bone metastasis is needed to develop more effective therapeutics for this disease. Herein, we reported that among the FZD family, FZD8 was robustly upregulated in bone-metastastic PCa cell lines and tissues. High levels of FZD8 expression were significantly positively associated with clinical tumor progression and bone metastasis. Furthermore, we found that overexpressing FZD8 promoted, whereas silencing FZD8 suppressed, PCa cell migration, invasion and stem cell-like phenotypes in vitro, through the activation of canonical Wnt/ß-catenin signaling. Importantly, downregulation of FZD8 greatly suppressed the incidence of PCa bone metastasis in vivo. Moreover, wild-type p53 transcriptionally repressed FZD8 by directly interacting with the FZD8 promoter. Taken together, these findings uncover a novel mechanism for PCa bone metastasis, and indicate that FZD8 might represent a potential therapeutic target for PCa bone metastasis.

Clinical Outcomes of Thymectomy in Myasthenia Gravis Patients with a History of Crisis.

BACKGROUND: The use of thymectomy in myasthenia gravis (MG) patients with a history of myasthenic crisis (MC) has not been well established. Here, we determined the efficacy of thymectomy by assessing the long-term clinical outcomes and reviewed thymectomy reports on MC patients. METHODS: Subjects included 31 patients who suffered at least one crisis before surgery, with a cumulative total 73 episodes of MC in Southern China between May 2000 and December 2010. Long-term follow-up was performed and clinical outcomes were evaluated. We used complete stable remission (CSR), termed an asymptomatic status without medication for at least 12 months; general complete remission (GCR), termed an asymptomatic status with or without some form of therapy excluding cholinesterase inhibitors, to assess patient outcomes. RESULTS: All patients underwent thymectomy with an overall complication rate of 16.1 % and a perioperative mortality rate of 3.2 %. Long-term follow-up occurred between 12.6 and 177 months, at which point 18 (58.1 %) patients experienced improved status, including one patient who achieved CSR; 13 (41.9 %) patients achieved GCR; 6 (19.4 %) showed unchanged status and one worse (3.2 %) status. The remaining 6 patients died, with 3 due to MG-related causes. Using a multivariate Cox regression analysis of GCR by characteristics, patients with better response to medical treatments before thymectomy were positively associated with GCR rates (p = 0.028). CONCLUSIONS: Extended transsternal thymectomy is a feasible and effective therapy for MG patients with crisis history, especially for those patients who have shown positive signs of remission after exhausting conventional medical treatments.

Identification and validation of AIB1 and EIF5A2 for noninvasive detection of bladder cancer in urine samples.

We previously demonstrated that amplified in breast cancer 1 (AIB1) and eukaryotic initiation factor 2 (EIF5A2) overexpression was an independent predictor of poor clinical outcomes for patients with bladder cancer (BCa). In this study, we evaluated the usefulness of AIB1 and EIF5A2 alone and in combination with nuclear matrix protein 22 (NMP22) as noninvasive diagnostic tests for BCa. Using urine samples from 135 patients (training set, controls [n = 50] and BCa [n = 85]), we detected the AIB1, EIF5A2, and NMP22 concentrations using enzyme-linked immunosorbent assay. We applied multivariate logistic regression analysis to build a model based on the three biomarkers for BCa diagnosis. The diagnostic accuracy of the three biomarkers and the model were assessed and compared by the area under the curve (AUC) of the receiver operating characteristic. We validated the diagnostic accuracy of these biomarkers and the model in an independent validation cohort of 210 patients. In the training set, urinary concentrations of AIB1, EIF5A2, and NMP22 were significantly elevated in BCa. The AUCs of AIB1, EIF5A2, NMP22, and the model were 0.846, 0.761, 0.794, and 0.919, respectively. The model had the highest diagnostic accuracy when compared with AIB1, EIF5A2, or NMP22 (p < 0.05 for all). The model had 92% sensitivity and 92% specificity. We obtained similar results in the independent validation cohort. AIB1 and EIF5A2 show promise for the noninvasive detection of BCa. The model based on AIB1, EIF5A2, and NMP22 outperformed each of the three individual biomarkers for detecting BCa.

Relationship of Oct-4 to malignant stage: a meta-analysis based on 502 positive/high Oct-4 cases and 522 negative/low case-free controls.

BACKGROUND: Octamer 4 (Oct-4), an important member of the POU domain transcription factor family, has been suggested to function as a master switch during differentiation of human somatic cells and more recently has come to be linked with neoplastic properties. The aim of this study was to evaluate the relationship between Oct-4 and cancer stage using a meta-analysis approach. MATERIALS AND METHODS: Relevant articles published as of May 2015 were retrieved from the following databases: PubMed, ISI Web of Knowledge, Embase, and Chinese National Knowledge Infrastructure (CNKI). The strengths of relationship for outcomes of interest were estimated based on odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 11 articles on Oct-4 and cancer staging that collectively included 502 positive/high Oct-4 cases and 522 negative/low case-free controls were chosen. Positive/high Oct-4 was significantly associated with cancer stage in several kinds of cancer. Specifically, positive/high Oct-4 was associated with cancer stage III/IV (fixed effects: OR = 1.53, 95% CI = 1.12-2.10), primary tumor (T3-4) (random effects: OR = 1.93, 95% CI = 0.99-3.77), and cancer grade of differentiation (intermediate-poor) (random effects: OR = 3.45, 95% CI = 1.5-7.61). CONCLUSIONS: These findings suggest that positive/high Oct-4 is more strongly linked to stage III/IV cancer and cancer grade of differentiation, and is correlated with malignant characteristics that lead to poor prognosis in different types of cancer, especially in Asian. Given variability related to ethnicity and differences in cancer types, additional studies are warranted to establish the generalizability of our findings.

L858R-positive lung adenocarcinoma with KRAS G12V, EGFR T790M and EGFR L858R mutations: A case report.

Improvement in the current understanding of the molecular basis of lung cancer at multiple levels, including the genetic, epigenetic and protein levels, has the potential to impact the diagnosis, prognosis and treatment of lung cancer. The mutation status of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) is known to be a predictor of the response to gefitinib in lung cancer. Furthermore, mutations in the EGFR and KRAS genes appear to be mutually exclusive. The present study reports a rare case of a patient harboring two EGFR mutations (L858R and T790M) and a KRAS mutation (G12V). The development of gefitinib resistance was detected in the subsequent treatment. The present study indicates that EGFR and KRAS mutational analysis should be recommended for all patients with non-small-cell lung carcinoma.

Lentivirus-mediated shRNA interference of clusterin blocks proliferation, motility, invasion and cell cycle in the ovarian cancer cells.

BACKGROUND: In a previous analysis on the patients with ovarian cancers, we have found that clusterin is a biomarker associated with ovarian cancer in vivo and may be a prognostic factor associated with adverse outcome. Here, we explored the effect of lentivirus-mediated shRNA interference of clusterin, investigated whether clusterin was associated with adverse outcome of ovarian cancer cells in vitro. METHODS: OVCAR-3 and TOV-21G cell lines were infected with the lentivirus for delivering clusterin shRNA, and the stably transfected cells were selected. The effect of clusterin silencing was detected by western blotting assay. The proliferation, clonability, migration, invasion and cell cycle of two cell lines were detected separately by MTT assay, clone formation assay, scratch assay, transwell assay and fluorescence-activated cell sorting. RESULTS: Following clusterin silencing with shRNA, the expression of clusterin in two cell lines were decreased. And the proliferation, clonability, migration, invasion of these two cell lines were down-regulated apparently. The cell cycle of two cell lines was disturbed, cells in G1 phase was increased, but cells in G2 and S phase was decreased. CONCLUSIONS: The expression of clusterin is significantly correlated with the biological characteristics of ovarian cancer cells, it may be a potential molecular for ovarian cancer treatment.

SGK3 (CISK) may induce tumor angiogenesis (Hypothesis).

Serum- and glucocorticoid-inducible protein kinase 3 (SGK3), also known as cytokine-independent survival kinase (CISK), encoded by chromosome 8q12.2, is a downstream mediator of phosphatidylinositol 3-kinase (PI3K) oncogenic signaling. As a downstream target of PI3K, SGK3 has been reported to mediate pivotal roles in oncogenic progress in various cancers, including breast cancer, ovarian cancer and hepatocellular carcinoma. Functionally parallel to v-akt murine thymoma viral oncogene homolog (AKT)/protein kinase B, SGK3 serves as a hallmark mediating glycogen synthase kinase-ß (GSK3-ß), B-cell lymphoma (Bcl)-2-associated death promoter, forkead family of transcription factors, Bcl-extra large, Bcl-2, mammalian target of rapamycin, C-X-C chemokine receptor type 4 (CXCR4) and numerous other molecules in cell proliferation, growth, survival, migration and even tumor angiogenesis. Tumor angiogenesis is recognized as an essential step for tumor growth, invasion and metastasis, and it has become an intriguing target for anticancer drug development for tumor investigators worldwide. An abundance of experiments have been performed to investigate the role of the phosphoinositide 3-kinase (PI3K)/AKT pathway in regulating tumor angiogenesis. The mechanism of angiogenesis regulated by the PI3K/AKT pathway is, to a certain extent, clear. Although a number of SGK3 target molecules, including CXCR4 and GSK3ß, have demonstrated potential roles in promoting angiogenesis, the exact association between angiogenesis and SGK3 remains unclear. Thus, we hypothesize that SGK3, parallel to AKT, may also be important in mediating angiogenesis. Identifying the role of SGK3 in tumor angiogenesis will certainly present a novel perspective on the malignant transformation of tumors, as well as a target for tumor therapy.