A New Landscape of Testing and Therapeutics in Metastatic Breast Cancer.

Predictive biomarker testing on metastatic breast cancer is essential for determining patient eligibility for targeted therapeutics. The National Comprehensive Cancer Network currently recommends assessment of specific biomarkers on metastatic tumor subtypes, including hormone receptors, HER2, and BRCA1/2 mutations, on all newly metastatic breast cancers subtypes; programmed death-ligand 1 on metastatic triple-negative carcinomas; and PIK3CA mutation status on estrogen receptor-positive carcinomas. In select circumstances mismatch repair protein deficiency and/or microsatellite insufficiency, tumor mutation burden, and NTRK translocation status are also testing options. Novel biomarker testing, such as detecting PIK3CA mutations in circulating tumor DNA, is expanding in this rapidly evolving arena.

An Interaction Network Driven Approach for Identifying Cervical, Endometrial, Vulvar Carcinomic Biomarkers and Their Multi-targeted Inhibitory Agents from Few Widely Available Medicinal Plants.

Differently expressed genes (DEGs) across cervical (CC), endometrial (EC), and vulvar carcinoma (VC) may serve as potential biomarkers for these progressive tumor conditions. In this study, DEGs of cervical (CC), endometrial (EC), and vulvar carcinoma (VC) were identified by microarray analysis. The interaction network between the identified 124 DEGs was constructed and analyzed to identify the hub genes and genes with high stress centrality. DEGs, namely, CDK1 and MMP9, were found to show highest degree and highest stress centrality respectively from the gene interaction network of 124 nodes and 1171 edges. DEG CDK1 is found to be overlapping in both cervical and endometrial carcinomic conditions while DEG MMP9 is found in vulvar carcinomic condition. Further, as it is studied that many phytochemicals play an important role as medicinal drugs, we have identified phytochemicals from few widely available medicinal plants and performed comprehensive computational study to identify a multi-targeted phytochemical against the identified DEGs, which are crucially responsible for the progression of these carcinomic conditions. Virtual screening of the phytochemicals against the target DEG protein structures with PDB IDs 4Y72 and 1GKC resulted in identifying the multi-targeted phytochemical against both the proteins. The molecular docking and dynamics simulation studies reveal that luteolin can act as a multi-targeted agent. Thus, the interactional and structural insights of luteolin toward the DEG proteins signify that it can be further explored as a multi-targeted agent against the cervical, endometrial, and vulvar carcinoma.

Yin Yang 1-stimulated long noncoding RNA bladder cancer-associated transcript 1 upregulation facilitates esophageal carcinoma progression via the microRNA-5590-3p/programmed cell death-ligand 1 pathway.

Esophageal carcinoma (EC) is a common gastrointestinal malignancy that poses a threat to public health worldwide. Long noncoding RNA (lncRNA) bladder cancer-associated transcript 1 (BLACAT1) exerts a tumorigenic role in several malignant tumors; nevertheless, its function in EC remains largely unknown. Besides, programmed cell death-ligand 1 (PD-L1), an oncogene in numerous human cancers, has been identified as a therapeutic target for EC. Therefore, we intended to explore the potential regulatory network involving BLACAT1 and PD-L1 in EC. In this study, we observed increased BLACAT1 and PD-L1 levels in EC tissues and EC cell lines. Moreover, YY1 could activate BLACAT1 transcription in EC cells (TE-1 and EC9706). In addition, in vitro and in vivo experiments demonstrated that BLACAT1 facilitated EC cell proliferation and metastasis and EC tumor growth. Also, the effects of BLACAT1 silencing on EC cell functions were partially reversed by PD-L1 overexpression. Besides, it was identified that BLACAT1 competed with PD-L1 to bind to miR-5590-3p in EC cells. Furthermore, miR-5590-3p suppression could abrogate the functional effects of BLACAT1 knockdown on EC cells; while PD-L1 silencing partly abolished the promoting effects of miR-5590-3p suppression on the biological functions of EC cells. To sum up, YY1-induced BLACAT1 accelerated EC progression via regulating the miR-5590-3p/PD-L1 axis.

A New Landscape of Testing and Therapeutics in Metastatic Breast Cancer.

Predictive biomarker testing on metastatic breast cancer is essential for determining patient eligibility for targeted therapeutics. The National Comprehensive Cancer Network currently recommends assessment of specific biomarkers on metastatic tumor subtypes, including hormone receptors, HER2, and BRCA1/2 mutations, on all newly metastatic breast cancers subtypes; programmed death-ligand 1 on metastatic triple-negative carcinomas; and PIK3CA mutation status on estrogen receptor-positive carcinomas. In select circumstances mismatch repair protein deficiency and/or microsatellite insufficiency, tumor mutation burden, and NTRK translocation status are also testing options. Novel biomarker testing, such as detecting PIK3CA mutations in circulating tumor DNA, is expanding in this rapidly evolving arena.

Anticancer and antimutagenic activity of Silybum marianum L. and Eucalyptus camaldulensis Dehnh. against skin cancer induced by DMBA: In vitro and in vivo models.

The current study investigated the prospective effect of Silybum marianum L. and Eucalyptus camaldulensis Dehnh extracts against skin cancer. Skin cancer was induced by 7,12-dimethylbenz(a) anthracene (DMBA) in young Balb/c mice. Plant extracts were administered to animals orally, once/day (100mg/kg, 5 days/week) for the 20 weeks. Anticancer activity was examined via tumor progression, where antimutagenic activity was measured using 8-OHdG and sister chromatid exchange (SCE) levels. Eucalyptus camaldulensis Dehnh. leaves extract and Silybum marianum L. leaves extract significantly reduced 8-OHdG in cultured human lymphocytes in a dose-response manner (P<0.05). Similarly, the leave extracts of both plants significantly reduced chromosomal damage as measured by SCE levels (P<0.05). In the skin painting assay, the leave extracts of both plants significantly delayed the onset of tumors compared to DMBA treated group (P<0.05). The Silybum marianum leaves extract significantly reduced tumor incidence (P<0.01) and papilloma frequency (P<0.01) induced by DMBA. The Eucalyptus camaldulensis leaves extract significantly reduced the number of tumors per animal (P<0.05) and incidence of tumors (P<0.001). The in vitro and in vivo findings showed that leaves of Silybum marianum L. and Eucalyptus camaldulensis Dehnh. extracts might be a promising source for anticancer and antimutagenic agents against human cancer.

Role of SMARCA4 (BRG1) and SMARCB1 (INI1) in Dedifferentiated Endometrial Carcinoma With Paradoxical Aberrant Expression of MMR in the Well-Differentiated Component: A Case Report and Review of the Literature.

INTRODUCTION: Dedifferentiated endometrial carcinoma is an uncommon highly aggressive uterine tumor. It comprises 2 components: a well-differentiated, low-grade epithelial carcinoma and an undifferentiated carcinoma. The undifferentiated carcinoma frequently exhibits rhabdoid cytologic features. Many of these tumors are characterized by an aberrant switch/sucrose non-fermenting (SWI/SNF) complex. They may also exhibit aberrant expression of mismatch repair (MMR) proteins. Together, these play an important role in the pathogenesis and aggressive nature of the tumor. MATERIAL AND METHODS: We present a case of dedifferentiated endometrial carcinoma in a 63-year-old female showing loss of expression of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4/BRG1), and aberrant expression of MMR proteins. We also review the literature starting from the earliest recognition of this entity and the various studies done to explain its molecular pathogenesis and prognostic importance. RESULTS AND CONCLUSIONS: Recognition of SWI/SNF complex-deficient dedifferentiated endometrial carcinoma is important as these tumors do not respond to platinum-based chemotherapy, and consideration of alternative therapies is often necessary. We also want to emphasize that though most of the studies have found MMR deficiency in the undifferentiated carcinoma component, it may be seen only in the low-grade, well-differentiated component, as observed in this case.

Hereditary vs Familial Pancreatic Cancer: Associated Genetic Syndromes and Clinical Perspective.

Pancreatic ductal adenocarcinoma (PDAC) is a disease marked by high rates of mortality; it is mostly incurable at the time of diagnosis. Only about 7% of patients survive 5 years after diagnosis. Diagnosis at a late stage and rapid progression with minimal response to available treatments are the main reasons for this poor outcome. It is crucial to identify individuals at high risk of developing PDAC so preventive and early detection measures can be employed. Approximately 10% to 15% of PDAC cases have a hereditary or familial basis. In the majority of PDAC cases, no main causative gene has been identified, but several known germline pathogenic mutations have been shown to be related to an increased risk of this cancer. The presence of 2 or more patients with pancreatic cancer within the circle of first-degree relatives, without the presence of a causative germline mutation, is defined as familial pancreatic cancer; this accounts for 4% to 10% of PDAC. Based on the growing evidence supporting the benefit of germline genetic testing in patients with PDAC, both the American Society of Clinical Oncology and the National Comprehensive Cancer Network recently updated their guidelines to include recommendations around genetic testing for patients with pancreatic cancer. However, there is no general consensus on the group of patients and individuals who should be studied and screened. We present a demonstrative case and review the available data on hereditary and familial PDAC.

Aristolochic acid mutational signature defines the low-risk subtype in upper tract urothelial carcinoma.

Rationale: Dietary exposure to aristolochic acids and similar compounds (collectively, AA) is a significant risk factor for nephropathy and subsequent upper tract urothelial carcinoma (UTUC). East Asian populations, who have a high prevalence of UTUC, have an unusual genome-wide AA-induced mutational pattern (COSMIC signature 22). Integrating mutational signature analysis with clinicopathological information may demonstrate great potential for risk ranking this UTUC subtype. Methods: We performed whole-genome sequencing (WGS) on 90 UTUC Chinese patients to extract mutational signatures. Genome sequencing data for urinary cell-free DNA from 26 UTUC patients were utilized to noninvasively identify the mutational signatures. Genome sequencing for primary tumors on 8 out of 26 patients was also performed. Metastasis-free survival (MFS) and cancer-specific survival (CSS) were measured using Kaplan-Meier methods. Results: Data analysis showed that a substantial proportion of patients harbored the AA mutational signature and were associated with AA-containing herbal drug intake, female gender, poor renal function, and multifocality. Field cancerization was found to partially contribute to multifocality. Nevertheless, AA Sig subtype UTUC patients exhibited favorable outcomes of CSS and MFS compared to the No-AA Sig subtype. Additionally, AA Sig subtype patients showed a higher tumor mutation burden, higher numbers of predicted neoantigens, and infiltrating lymphocytes, suggesting the potential for immunotherapy. We also confirmed the AA signature in AA-treated human renal tubular HK-2 cells. Notably, the AA subtype could be ascertained using a clinically applicable sequencing strategy (low coverage) in both primary tumors and urinary cell-free DNA as a basis for therapy selection. Conclusion: The AA mutational signature as a screening tool defines low-risk UTUC with therapeutic relevance. The AA mutational signature, as a molecular prognostic marker using either ureteroscopy and/or urinary cell-free DNA, is especially useful for diagnostic uncertainty when kidney-sparing treatment and/or immune checkpoint inhibitor therapy were considered.

Characterization of therapy-related acute leukemia in hereditary breast-ovarian carcinoma patients: role of BRCA1 mutation and topoisomerase II-directed therapy.

Therapy-related acute leukemias (t-ALs) represent approximately 10-20% of all acute leukemias, are frequently resistant to chemotherapy, and are associated with guarded outcomes. The national comprehensive cancer network data suggest that t-AL cases are diagnosed at increasing rates in breast cancer patients treated with chemotherapeutic agents targeting topoisomerase II. Two cases of BRCA1-mutated ovarian and breast carcinoma who developed therapy-related APL and ALL, respectively, following topoisomerase II-directed therapy were characterized. Genomic characterization of therapy-related acute promyelocytic leukemia (t-APL) revealed a unique RARA intron 2 breakpoint (Chr17: 40347487) at 3'-end of RARA corroborating breakpoint clustering in t-APL following topoisomerase II inhibition. Both cases of this series harbored germline BRCA1 mutations. The germline BRCA1 mutation in patient with t-APL was detected in exon 8 (HGVS nucleotide: c.512dupT). This mutation in t-APL is extremely rare. Interestingly, t-ALL patient in this series had a BRCA1 mutation (HGVS nucleotide: c.68_69delAG; BIC designation: 187delAG) identical to a previously reported case after the treatment of same primary disease. It is unlikely that two breast cancer patients with identical BRCA1 mutation receiving topoisomerase II-targeted agents for the primary disease developed t-AL by chance. This report highlights the development of t-AL in BRAC1-mutated hereditary breast and ovarian cancer patients and warrants further studies on functional consequences of topoisomerase inhibition in this setting.

Clinical relevance of gene expression in localized and metastatic prostate cancer exemplified by FABP5.

PURPOSE: Fatty acid-binding protein 5 (FABP5), a transport protein for lipophilic molecules, has been proposed as protein marker in prostate cancer (PCa). The role of FABP5 gene expression is merely unknown. METHODS: In two cohorts of PCa patients who underwent radical prostatectomy (n = 40 and n = 57) and one cohort of patients treated with palliative transurethral resection of the prostate (pTUR-P; n = 50) FABP5 mRNA expression was analyzed with qRT-PCR. Expression was correlated with clinical parameters. BPH tissue samples served as control. To independently validate findings on FABP5 expression, three microarray and sequencing datasets were reanalyzed (MSKCC 2010 n = 216; TCGA 2015 n = 333; mCRPC, Nature Medicine 2016 n = 114). FABP5 expression was correlated with ERG-fusion status, TCGA subtypes, cancer driver mutations and the expression of druggable downstream pathway components. RESULTS: FABP5 was overexpressed in PCa compared to BPH in the cohorts analyzed by qRT-PCR (radical prostatectomy p = 0.003, p = 0.010; pTUR-P p = 0.002). FABP5 expression was independent of T stage, Gleason Score, nodal status and PSA level. FABP5 overexpression was associated with the absence of TMPRSS2:ERG fusion (p < 0.001 in TCGA and MSKCC). Correlation with TCGA subtypes revealed FABP5 overexpression to be associated with SPOP and FOXA1 mutations. FABP5 was positively correlated with potential drug targets located downstream of FABP5 in the PPAR-signaling pathway. CONCLUSION: FABP5 overexpression is frequent in PCa, but seems to be restricted to TMPRESS2:ERG fusion-negative tumors and is associated with SPOP and FOXA1 mutations. FABP5 overexpression appears to be indicative for increased activity in PPAR signaling, which is potentially druggable.

Colorectal cancer peritoneal metastases: Biology, treatment and next steps.

The presence of peritoneal metastases in patients with advanced colorectal cancer is associated with poor prognosis but the mechanisms for this are unclear. This review summarises the current knowledge of the pathophysiology, clinical features, prevalence, prognosis, and molecular biology of peritoneal metastases and the risk factors for the development of peritoneal metastases following resection of a primary colorectal tumour. Furthermore, the evidence for treatment strategies are described including cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, early post-operative intraperitoneal chemotherapy, sequential post-operative intraperitoneal chemotherapy and emerging novel strategies. Active areas of research should include the identification of individuals at high risk of peritoneal metastases after curative resection of primary tumour, development of a surveillance program for high-risk patients, optimisation of systematic therapies and further investigation of the use of intraperitoneal chemotherapy.

Coix lacryma-jobi var. ma-yuen Stapf sprout extract induces cell cycle arrest and apoptosis in human cervical carcinoma cells.

BACKGROUND: Cervical cancer is the second-leading cause of cancer-related mortality in females. Coix lacryma-jobi L. var. ma-yuen (Rom.Caill.) Stapf ex Hook. f. is the most widely recognized medicinal herb for its remedial effects against inflammation, endocrine system dysfunctions, warts, chapped skin, rheumatism, and neuralgia and is also a nourishing food. METHODS: To investigate the activity of Coix lacryma-jobi sprout extract (CLSE) on cell proliferation in human cervical cancer HeLa cells, we conducted a Cell Counting Kit-8 (CCK-8) assay. Flow-cytometric analysis and western blot analysis were performed to verify the effect of CLSE on the regulation of the cell cycle and apoptosis in HeLa cells. RESULTS: We observed that CLSE significantly inhibited cell proliferation. Furthermore, CLSE dose-dependently promoted cell cycle arrest at the sub-G1/ S phase in HeLa cells, as detected by bromodeoxyuridine (BrdU) staining. The cell-cycle-arrest effects of CLSE in HeLa cells were associated with downregulation of cyclin D1 and cyclin-dependent kinases (CDKs) 2, 4, and 6. Moreover, CLSE induced apoptosis, as determined by flow-cytometric analysis and nuclear DNA fragmentation with Annexin V/propidium iodide (PI) and 4'6'-diamidino-2-phenylindole (DAPI) staining. Induction of apoptosis by CLSE was involved in inhibition of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) and upregulation of the apoptotic proteins p53, cleaved poly (ADP-ribose) polymerase (PARP), cleaved caspase-3, and cleaved caspase-8. Finally, we observed that CLSE inactivated the phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) pathways. CONCLUSIONS: CLSE causes cell cycle arrest and apoptotic cell death through inactivation of the PI3K/AKT pathway in HeLa cells, suggesting it is a viable therapeutic agent for cervical cancer owing to its anticancer effects.

Theaflavin-3,3'-Digallate Suppresses Human Ovarian Carcinoma OVCAR-3 Cells by Regulating the Checkpoint Kinase 2 and p27 kip1 Pathways.

Theaflavin-3,3'-digallate (TF3) is a unique polyphenol in black tea. Epidemiological studies have proved that black tea consumption decreases the incidence rate of ovarian cancer. Our former research demonstrated that TF3 inhibited human ovarian cancer cells. Nevertheless, the roles of checkpoint kinase 2 (Chk2) and p27 kip1 (p27) in TF3-mediated inhibition of human ovarian cancer cells have not yet been investigated. In the current study, TF3 enhanced the phosphorylation of Chk2 to modulate the ratio of pro/anti-apoptotic Bcl-2 family proteins to initiate intrinsic apoptosis in a p53-independent manner and increased the expression of death receptors to activate extrinsic apoptosis in OVCAR-3 human ovarian carcinoma cells. In addition, TF3 up-regulated the expression of p27 to induce G0/G1 cell cycle arrest in OVCAR-3 cells. Our study indicated that Chk2 and p27 were vital anticancer targets of TF3 and provided more evidence that TF3 might be a potent agent to be applied as adjuvant treatment for ovarian cancer.

Antrodia salmonea-induced oxidative stress abrogates HER-2 signaling cascade and enhanced apoptosis in ovarian carcinoma cells.

Antrodia salmonea is well known in Taiwan as a traditional Chinese medicinal fungus and has demonstrated antioxidant, anti-inflammatory, and anticancer effects. However, the anticancer activity of A. salmonea against human ovarian cancer is still elusive. Therefore, we investigated the antiovarian tumor activity of a fermented culture broth of A. salmonea and exhibits its underlying molecular mechanism. A. salmonea shows a significant effect on cell viability in human ovarian carcinoma (SKOV-3 or A2780) cell lines with an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Increased terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells and annexin V-propidium iodide stained cells indicate that A. salmonea induces late apoptosis in SKOV-3 cells. Notably, treatment with A. salmonea induced the following events: Apoptosis; caspase-3, -8, -9 and poly(ADP-ribose) polymerase activation; first apoptosis signal (Fas) and Fas ligand activation; Bid cleavage; and Bax2-B-cell lymphoma 2 dysregulation. The results show that A. salmonea-induced apoptosis was mediated by both mitochondrial and death receptor pathways. An increase in intracellular reactive oxygen species (ROS) was also observed in A. salmonea-treated cells, whereas the antioxidant N-acetylcysteine (NAC) prevented A. salmonea-induced cell death and DNA fragmentation, indicating that A. salmonea-induced apoptosis was mediated by ROS generation. Interestingly, A. salmonea-induced apoptosis is associated with the suppression of human epidermal growth factor receptor-2 (HER-2/neu) and phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) expression in HER-2/neu overexpressing SKOV-3 cells. NAC significantly prevented A. salmonea-induced HER-2/neu depletion and PI3K/AKT inactivation, indicating that A. salmonea-triggered apoptosis is mediated by ROS-inhibited HER-2/neu signaling cascades. To our knowledge, this is the first report describing the anticancer activity of this potentially beneficial mushroom against human ovarian carcinoma.

Curcumol attenuates epithelial-mesenchymal transition of nasopharyngeal carcinoma cells via TGF-ß1.

The current study aimed to identify the effect and primary mechanism of Curcumol on the migration of nasopharyngeal carcinoma (NPC) cells in vitro and in vivo. Curcumol was dissolved in absolute ethyl alcohol and the experiment was performed in NPC 5­8F cells in vitro and in vivo. The effect of different concentrations of Curcumol on cell migration was determined using wound healing and Transwell assays. A cell counting kit­8 (CCK­8) assay was also performed in order to determine cell viability. Flow cytometry was used to detect the effect of Curcumol on apoptosis. The expression of epithelial­mesenchymal transition (EMT)­associated proteins and genes was evaluated by western blotting, reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and ELISA. In addition, the antitumor activity of Curcumol was investigated in female BALB/C nude mice with orthotopic tumor implants. The results indicated that cell apoptosis was increased and the viability of NPC 5­8F cells was decreased following treatment with Curcumol at doses of 0.1, 0.2 and 0.4 µM/ml. The results of in vivo experiments indicated that tumor growth and weight were decreased following Curcumol administration. Furthermore, the results of western blotting and RT­qPCR demonstrated that Curcumol altered the level of E­cadherin and N­cadherin in a dose­dependent manner in vivo. Curcumol also regulated the secretion of protein markers in the serum that were associated with EMT and TGF­ß1 in the 5­8F xenograft mouse model. Thus, the results indicated that Curcumol induced TGF­ß1­mediated EMT arrest by regulating E­cadherin and N­cadherin, which may prevent further development of NPC.

Gastric Carcinomas With Lymphoid Stroma: An Evaluation of the Histopathologic and Molecular Features.

Gastric carcinoma with lymphoid stroma is an uncommon variant enriched for mutually exclusive Epstein-Barr virus (EBV) positivity and mismatch repair (MMR) deficiency. We performed this study to evaluate molecular alterations in this morphologically homogeneous subtype and compare them with 295 conventional gastric cancers analyzed in The Cancer Genome Atlas study. We identified 31 study cases and subjected them to in situ hybridization for EBV-encoded RNAs and assessment for MMR status. Immunostains for PD-L1, ß-catenin, and HER2 were performed; extracted DNA was sequenced with a Comprehensive Cancer Panel. Most study patients were older adult men with stage I or II disease (76%). Tumors were classified as EBV/MMR-proficient (MMR-P) (n=7), EBV/MMR deficient (n=12), and EBV/MMR-P (n=12). EBV/MMR-P tumors were usually located in the proximal stomach (83%) and showed heterogenous growth patterns with glandular differentiation (83%). Tumors in all groups showed numerous tumor infiltrating lymphocytes and PD-L1 expression, infrequent nuclear ß-catenin accumulation (10%), and lacked both membranous HER2 staining and HER2 amplification. EBV/MMR-deficient tumors showed significantly higher tumor mutation burden (P=0.001) and KRAS alterations (56%) compared with EBV/MMR-P tumors (9%, P=0.05). TP53 variants were more common among EBV/MMR-P tumors (82%) compared with EBV/MMR proficient (0%, P=0.01) and EBV/MMR-deficient (11%, P<0.01) tumors. Alterations in KRAS, ARID1A, PIK3CA, and TP53 followed similar patterns of distribution compared with The Cancer Genome Atlas dataset. We conclude that gastric carcinomas with lymphoid stroma show a spectrum of molecular changes and frequent PD-L1 expression, raising the possibility that this subgroup of tumors may be susceptible to checkpoint inhibitors and/or agents that target receptor tyrosine kinase-mediated signaling.

Predictive factors of outcome in poorly differentiated thyroid carcinomas.

BACKGROUND: The prognosis of poorly differentiated thyroid carcinomas (PDTC) is heterogeneous though generally poor. The objectives of this study were to identify clinical and molecular factors of poor prognosis. METHODS: One hundred four consecutive patients treated for a PDTC between 01/01/2000 and 31/12/2010 were included in this study. A pathological review was done for all cases (blinded to clinical data and outcome). RESULTS: All patients underwent thyroidectomy. Adjuvant radioactive-iodine was administered in 95.2% of them. Tumours were pT3 or pT4 in 68.3% of cases and metastatic in 38.5% of patients. Extrathyroidal extension (ETE) was observed in 40% of patients. At the end of the initial treatment, only 37% of patients were considered in remission. Fifty-two patients (50%) became refractory to radioiodine during follow-up. The 5-year overall survival was 72.8% and the 5-year recurrence-free survival (RFS) was 45.3%. Remission after initial treatment was an independent factor of RFS (HR = 0.22; [0.10-0.49]). ETE was the only significant parameter influencing the overall survival in multivariate analysis. TERT promoter mutations at positions -124 (C228T) and -146 (C250T) were present in 38.1% of analysed patients and significantly associated with radioiodine resistance but not with overall survival. Half of TERT promoter mutant tumours harboured also RAS or BRAF mutations. CONCLUSION: PDTC form a heterogeneous group of patients with usual late-stage diagnosis, low radioactive iodine avidity and frequent metastatic spread. TERT promoter mutations could help to identify patients with high risk of radio-iodine refractoriness.

Toosendanin suppresses oncogenic phenotypes of human gastric carcinoma SGC­7901 cells partly via miR­200a­mediated downregulation of ß-catenin pathway.

Aberrant activation of ß-catenin signaling due to low expression of miR­200a is found in gastric carcinoma (GC) tissues promoting GC evolution. Toosendanin (TSN) has exhibited antitumor effects on various human cancer cells, but its influence on GC is largely unidentified. The potential roles of TSN on GC cells were examined and it was found that TSN inhibited growth, migration, invasion and TGF­ß1-induced epithelial-mesenchymal transition (EMT) and induced cell cycle arrest and apoptosis in SGC­7901 cells which were most sensitive to TSN among various GC cell lines. TSN also inactivated ß-catenin pathway in SGC­7901 cells and the above effects were reversed following induction of ß-catenin overexpression. Moreover, TSN facilitated the level of miR­200a which targets ß-catenin and miR­200a silencing attenuated the antitumor effects of TSN on SGC­7901 cells. Nonetheless, knockdown of miR­200a did not relieve the suppressive effects of TSN on p­AKT, p­ERK and p­GSK3ß which were upstream regulators of ß-catenin. In addition, TSN administration inhibited growth and liver metastasis of orthotopically implanted SGC­7901 tumors in vivo through miR­200a­mediated ß-catenin pathway. Our data suggest that TSN may suppress oncogenic phenotypes of human GC cells partly via miR­200a/ß-catenin axis. Hence, TSN may have a promising chemotherapeutic activity for GC therapy.

Rubus idaeus Inhibits Migration and Invasion of Human Nasopharyngeal Carcinoma Cells by Suppression of MMP-2 through Modulation of the ERK1/2 Pathway.

Nasopharyngeal carcinoma (NPC) is characterized by a high incidence of metastasis in the neck lymph nodes, resulting in a poor prognosis and posing challenges for treatment. In this study, we investigated the in vitro antimetastatic properties of Rubus idaeus extract (RIE) on human nasopharyngeal carcinoma cells. HONE-1, NPC-39 and NPC-BM cells were subjected to RIE treatment, and effects on the migration and invasion of tumor cells were analyzed. The results showed that RIE suppressed the migration and invasion of NPC cells. Gelatin zymography assay, Western blotting and real-time PCR showed that matrix metalloproteinases-2 (MMP-2) enzyme activity, protein expression and mRNA levels were down-regulated by RIE treatment. To identify the signaling pathway, mitogen-activated protein kinase proteins were examined, which showed that phosphorylation of ERK1/2 was inhibited after the treatment of RIE. In summary, our data showed that RIE inhibited the migration and invasion of NPC cells by suppressing the expression of MMP-2 by down-regulating the ERK1/2 signaling pathway, suggesting that Rubus idaeus may serve as chemotherapeutic and chemopreventive agent for NPC.