Acetyl-cinobufagin suppresses triple-negative breast cancer progression by inhibiting the STAT3 pathway.

BACKGROUND: The incidence of breast cancer (BC) worldwide has increased substantially in recent years. Epithelial-mesenchymal transition (EMT) refers to a crucial event impacting tumor heterogeneity. Although cinobufagin acts as an effective anticancer agent, the clinical use of cinobufagin is limited due to its strong toxicity. Acetyl-cinobufagin, a pre-drug of cinobufagin, was developed and prepared with greater efficacy and lower toxicity. METHODS: A heterograft mouse model using triple negative breast cancer (TNBC) cell lines, was used to evaluate the potency of acetyl-cinobufagin. Signal transducer and stimulator of transcription 3 (STAT3)/EMT involvement was investigated by gene knockout experiments using siRNA and Western blot analysis. RESULTS: Acetyl-cinobufagin inhibited proliferation, migration, and cell cycle S/G2 transition and promoted apoptosis in TNBC cells in vitro. In general, IL6 triggered the phosphorylation of the transcription factor STAT3 thereby activating the STAT3 pathway and inducing EMT. Mechanistically, acetyl-cinobufagin suppressed the phosphorylation of the transcription factor STAT3 and blocked the interleukin (IL6)-triggered translocation of STAT3 to the cell nucleus. In addition, acetyl-cinobufagin suppressed EMT in TNBC by inhibiting the STAT3 pathway. Experiments in an animal model of breast cancer clearly showed that acetyl-cinobufagin was able to reduce tumor growth. CONCLUSIONS: The findings of this study support the potential clinical use of acetyl-cinobufagin as a STAT3 inhibitor in TNBC adjuvant therapy.

Identification of RET fusions in a Chinese multicancer retrospective analysis by next-generation sequencing.

Fusion of RET with different partner genes has been detected in papillary thyroid, lung, colorectal, pancreatic, and breast cancer. Approval of selpercatinib for treatment of lung and thyroid cancer with RET gene mutations or fusions calls for studies to explore RET fusion partners and their eligibility for RET-based targeted therapy. In this study, RET fusion patterns in a large group of Chinese cancer patients covering several cancer types were identified using next-generation sequencing. A total of 44 fusion patterns were identified in the study cohort with KIF5B, CCDC6, and ERC1 being the most common RET fusion partners. Notably, 17 novel fusions were first reported in this study. Prevalence of functional RET fusions was 1.05% in lung cancer, 6.03% in thyroid cancer, 0.39% in colorectal cancer, and less than 0.1% in gastric cancer and hepatocellular carcinoma. Analysis showed a preference for fusion partners in different tumor types, with KIF5B being the common type in lung cancer, CCDC6 in thyroid cancer, and NCOA4 in colorectal cancer. Co-occurrence of EGFR mutations and RET fusions with rare partner genes (rather than KIF5B) in lung cancer patients was correlated with epidermal growth factor receptor-tyrosine kinase inhibitor resistance and could predict response to targeted therapies. Findings from this study provide a guide to clinicians in determining tumors with specific fusion patterns as candidates for RET targeted therapies.

C1632 suppresses the migration and proliferation of non-small-cell lung cancer cells involving LIN28 and FGFR1 pathway.

Chemoresistance and migration represent major obstacles in the therapy of non-small-cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancer patients in clinic. In the present study, we report that the compound C1632 is preferentially distributed in the lung after oral administration in vivo with high bioavailability and limited inhibitory effects on CYP450 isoenzymes. We found that C1632 could simultaneously inhibit the expression of LIN28 and block FGFR1 signalling transduction in NSCLC A549 and A549R cells, resulting in significant decreases in the phosphorylation of focal adhesion kinase and the expression of matrix metalloproteinase-9. Consequently, C1632 effectively inhibited the migration and invasion of A549 and A549R cells. Meanwhile, C1632 significantly suppressed the cell viability and the colony formation of A549 and A549R cells by inhibiting DNA replication and inducing G0/G1 cell cycle arrest. Interestingly, compared with A549 cells, C1632 possesses the same or even better anti-migration and anti-proliferation effects on A549R cells, regardless of drug resistance. In addition, C1632 also displayed the capacity to inhibit the growth of A549R xenograft tumours in mice. Altogether, these findings reveal the potential of C1632 as a promising anti-NSCLC agent, especially for chemotherapy-resistant NSCLC treatment.

The Cancers-Specific Survival of Metastatic Pulmonary Carcinoids and Sites of Distant Metastasis: A Population-Based Study.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths and pulmonary carcinoids (PCs) account for almost 2% of all pulmonary malignancies. However, few published articles have reported prognosis and related factors of pulmonary carcinoid patients. MATERIAL AND METHOD: The Surveillance, Epidemiology, and End Results (SEER) database was used to collect data of patients diagnosed with metastatic PCs from 2010 to 2016. The prognosis and survival of these patients were compared by employing Cox proportional hazards and the Kaplan-Meier survival analysis. RESULTS: A total of 1763 patients were analyzed. The liver (668, 25.6%) was shown to be the most common metastatic site in the isolated organ metastasis cohort, followed by the lung (636, 24.4%), bone (562, 21.6%), and brain (460, 17.6%). Among the patients, the tumor metastasized to a single distant site included the liver, bone, lung, and brain. Cancer-specific survival (CSS) in metastatic PCs is determined by the site of metastasis and the total number of such sites. Pulmonary carcinoid patients with isolated liver metastasis manifested more favorable survival rates in comparison to patients having isolated metastasis in the lung, brain, or bone. The median CSS was 45, 7, 6, 5 months (P = 0.011). The number of distant metastatic sites and the location of distant metastasis were found to be independent risk factors for CSS. For patients with distant isolated metastasis, liver metastasis (P < 0.0001) had better CSS in comparison to those with bone metastasis. When compared to patients whose carcinoids had metastasized to the bones, patients with a brain (P = 0.273) or lung (P = 0.483) metastasis had the same CSS. CONCLUSION: Cancer-specific survival in metastatic PCs depends on the site of metastasis and the total number of such locations. PC patients with isolated liver metastasis manifested more favorable survival in comparison to patients with isolated metastasis in the lung, brain, or bone.

Case Report: Next-Generation Sequencing Reveals Tumor Origin in a Female Patient With Brain Metastases.

BACKGROUND: Brain metastasis mainly originates from lung cancer. Napsin A and TTF-1 factors have frequently been detected in lung adenocarcinoma cases. Brain metastasis tumors with napsin A and TTF-1 positive are easily classified as lung adenocarcinoma origin. However, some thyroid cancers also exhibit these clinical features. Besides, lung is the most common metastasis of undifferential thyroid cancer. Therefore, it requires development of novel diagnostic tools to aid in distinguishing between pulmonary and thyroid origin. PATIENT FINDINGS: We reported a case that was initially diagnosed as brain metastatic lung cancer based on immunohistochemistry results. Analysis of next-generation sequencing (NGS) data from the brain lesion revealed that the cancer may have originated from the thyroid. We detected combo mutations in TERT promoter mutation, RET fusion and TP53, which are common in undifferential thyroid cancer (UTC), but rare for lung cancer. These results, coupled with identification of PAX8, indicated that this patient had UTC. Additionally, her three sons, despite being asymptomatic, were all diagnosed with papillary thyroid carcinoma. SUMMARY: The patient received anlotinib treatment and showed good clinical outcomes. One month after anlotinib treatment, the pulmonary nodules were found to be controlled, and the thyroid tumor drastically reduced, and tracheal compression relieved. She continued anlotinib treatment for the following two months, but died one month later because the treatment stopped owing to financial reasons. All her sons underwent total thyroidectomy with lymph node dissection. CONCLUSIONS: Although NGS has been reported to assist in diagnosis of the origin of some tumors, this is the first evidence of NGS for the determination of the origin of thyroid tumors. To our knowledge, this is the first time that a combination of multiple mutations has been used to help determine the origin of a tumor, compared with the previous single mutant gene. Moreover, this is the first evidence on the use of anlotinib for treatment of UTC with distant metastasis. Besides, all three sons of the patient had thyroid carcinoma in subsequent examinations, indicating high-risk for familial non-medullary thyroid cancer in UTC patients and necessity for performing thyroid ultrasound testing in other family members.

Survival nomogram for patients with metastatic siewert type II adenocarcinoma of the esophagogastric junction: a population-based study.

BACKGROUND: The aim of this study was to construct a nomogram to predict the survival of patients with metastatic Siewert Type II adenocarcinomas of the esophagogastric junction (AEG). METHODS: Patients were identified using the Surveillance, Epidemiology, and End Results (SEER) database. Cox regression analysis was performed to assess the prognostic factors. A nomogram comprising independent prognostic factors was established and evaluated using C-indexes, calibration curves, and decision curve analyses. RESULTS: In total 1616 eligible patients were enrolled. Race, age, bone metastasis, liver metastasis, lung metastasis, other metastasis sites, and distant lymph nodes metastasis were independent prognostic factors and were integrated to construct the nomogram. The nomogram had a C-index of 0.590 (95% CI: 0.569-0.611) in the training cohort and 0.569 (95% CI: 0.532-0.606) in the validation cohort. The calibration plots for the probabilities of 6-month and 1-year overall survival demonstrated there was an optimum between nomogram prediction and actual observation. CONCLUSION: We developed and validated a nomogram to predict individual prognosis for patients with metastatic Siewert Type II AEG, and the risk stratification system based on the nomogram could effectively stratify the patients into two risk subgroups, which can help clinicians accurately predict mortality risk and recommend personalized treatment modalities.

Sites of distant metastases and the cancer-specific survival of metastatic Siewert type II esophagogastric junction adenocarcinoma: a population-based study.

BACKGROUND: The effect of distant metastasis on prognosis in patients with Siewert type II adenocarcinoma of the esophagogastric junction (AEG) remains elusive. METHODS: Patients diagnosed as metastatic Siewert type II AEG were identified using the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival analysis and a Cox proportional hazards analysis were performed to assess the effect of distant metastases sites. RESULTS: We analyzed 1616 eligible patients. Liver was the most frequent metastatic site. For patients with isolated distant metastasis, the median survival time was 8, 7, 8, 10, and 11 months for patients with liver, bone, brain, lung, and distant lymph nodal metastasis, respectively (p = 0.011). The number of metastatic sites and the site of distant metastasis were independent prognostic factors for cancer-specific survival (CSS). In patients with isolated distant metastasis, using bone metastasis as reference, lung (p = 0.011) or distant lymph node metastasis (p = 0.030) was associated with better CSS, while patients with liver (p = 0.051) or brain (p = 0.488) metastasis had similar CSS compared to patients with bone metastasis. CONCLUSION: CSS in metastatic Siewert type II AEG is dependent on the metastatic site and the number of metastatic sites.

Mechanism of epithelial­mesenchymal transition inhibited by miR­203 in non­small cell lung cancer.

The aim of the present study was to investigate whether miR­203 can inhibit transforming growth factor­ß (TGF­ß)­induced epithelial­mesenchymal transition (EMT), and the migration and invasion ability of non­small cell lung cancer (NSCLC) cells by targeting SMAD3. In the present study, the expression levels of miR­203, SMAD3 mRNA and protein in NSCLC tissues were examined, as well as their corresponding paracancerous samples. The miR­203 mimics and miR­203 inhibitor were transfected into the H226 cell line. RT­qPCR was used to assess the expression levels of E­cadherin, Snail, N­cadherin and vimentin mRNA, and western blotting was performed to detect the expression levels of p­SMAD2, SMAD2, p­SMAD3, SMAD3 and SMAD4. The cell migration and invasion abilities were detected by Transwell assays. The target site of SMAD3 was predicted by the combined action between miR­203 and dual luciferase. The results revealed that the RNA levels of miR­203, compared with paracancerous tissues, were decreased in NSCLC tissues, while SMAD3 mRNA and protein levels were upregulated, and miR­203 inhibited SMAD3 expression. Induction of TGF­ß led to decreased E­cadherin mRNA levels, upregulation of Snail, N­cadherin and vimentin mRNA levels (P<0.05), and significant increase in cell migration and invasion, whereas transfection of miR­203 mimics reversed the aforementioned results (P<0.05). Conversely, miR­203 inhibitor could further aggravate the aforementioned results (P<0.05). Western blot results revealed that transfection of miR­203 mimics significantly reduced the protein expression of SMAD3 and p­SMAD3 (P<0.05). Furthermore, the results of the Dual­Luciferase assay revealed that miR­203 inhibited SMAD3 expression by interacting with specific regions of its 3'­UTR. Overall, a novel mechanism is revealed, in which, miR­203 can inhibit SMAD3 by interacting with specific regions of the 3'­UTR of SMAD3, thereby restraining TGF­ß­induced EMT progression and migration and invasion of NSCLC cells.

Clinical features and prognosis of primary tracheal small cell carcinoma: a population-based analysis.

BACKGROUND: Primary tracheal small cell carcinoma (SCC) is an uncommon malignancy; therefore, its clinical features and prognosis are still unclear. METHODS: We used the population-based Surveillance, Epidemiology, and End Results (SEER) database to elucidate the clinical features and prognosis of primary tracheal SCC. The clinical features were assessed by using the chi-square test. Overall survival (OS) was computed using the Kaplan-Meier method, and a Cox proportional hazards analysis was performed to evaluate the prognostic factors. RESULTS: From 1973 to 2015, 1,392 primary tracheal tumor cases were reported in the SEER database, 75 (5.4%) of which were SCC. Age, sex, race, extent of disease, lymph node involvement, surgery and radiation treatment were similar between patients with SCC and those with squamous cell carcinoma (SQC), but patients with SCC were more likely to receive chemotherapy (65.8% vs. 28.2%, respectively; P<0.001). The 1-, 3- and 5-year OS rates of patients with SCC were 37.8%, 12.4% and 7.1%, respectively, and the median survival duration was 10.0 months, which was much worse than that observed for patients with other histopathological types of tracheal cancer. Among patients aged 60-100 years and those with regional lymph node involvement, the OS for patients with SQC was superior to that for patients with SCC (P=0.034 and P=0.016, respectively). According to the multivariate analysis, age and lymph node involvement are independent prognostic factors of SCC. CONCLUSION: Primary tracheal SCC is a rare carcinoma with a poor prognosis. Age and lymph node involvement are independent prognostic factors of SCC.

Down-regulation of MTHFD2 inhibits NSCLC progression by suppressing cycle-related genes.

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a bifunctional enzyme located in the mitochondria. It has been reported to be overexpressed in several malignancies. However, the relationship between the expression of MTHFD2 and non-small cell lung cancer (NSCLC) remains largely unknown. In this study, we found that MTHFD2 was significantly overexpressed in NSCLC tissues and cell lines. Knockdown of MTHFD2 resulted in reduced cell growth and tumorigenicity in vitro and in vivo. Besides, the mRNA and protein expression level of cell cycle genes, such as CCNA2, MCM7 and SKP2, was decreased in MTHFD2 knockdown H1299 cells. Our results indicate that the inhibitory effect of MTHFD2 knockdown on NSCLC may be mediated via suppressing cell cycle-related genes. These findings delineate the role of MTHFD2 in the development of NSCLC and may have potential applications in the treatment of NSCLC.

Gephyrin suppresses lung squamous cell carcinoma development by reducing mTOR pathway activation.

Background: The mTOR pathway is altered in a multitude of cancers, including lung cancer; however, abnormal activation in this pathway is less common in lung adenocarcinoma (LUAD) than in lung squamous cell carcinoma (LUSC). Gephyrin is a highly conserved and widely expressed ancient protein in vertebrate tissues. Its role and molecular mechanism in lung cancer development are largely unknown. Method: We analyzed the expression profile of gephyrin and overall survival rates in LUAD and LUSC. The LUSC cells (H520 and SK-MES-1) were transfected with pLV-gephyrin to establish gephyrin stable overexpression cell lines. Real-time quantitative PCR and Western blot were performed to detect the mRNA and protein levels. The cell growth and cell cycle were detected by the MTT assay and flow cytometry. Finally, a xenograft tumor model was established to determine cell tumorigenesis in vivo. Results: Our results show that gephyrin was reduced in LUAD and LUSC, and its low expression in LUSC patients indicated poor prognosis. Gephyrin overexpression suppressed LUSC cell proliferation, arrested cell cycle progression, and decreased the expression of cell-cycle related proteins such as cyclin D1, cyclin-dependent kinase-2 (CDK2), and proliferation-related protein proliferating cell nuclear antigen (PCNA). Conversely, knockdown of gephyrin promoted LUSC cell growth. Moreover, gephyrin reduced mTOR pathway activation to inhibit cyclin D1 and CDK2 translation. Mechanistically, gephyrin suppressed mTOR pathway activation by promoting mTOR degradation. Furthermore, gephyrin overexpression suppressed LUSC tumorigenesis. Conclusion: Gephyrin suppressed LUSC development by reducing mTOR pathway activation, implicating gephyrin as a potential molecular target for LUSC management.

Tumor shrinkage rate as a potential marker for the prediction of long-term outcome in advanced non-small cell lung cancer treated with first-line tyrosine kinase inhibitors.

CONTEXT: Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) play an indispensable role in the treatment of non-small cell lung cancer (NSCLC), leading to a survival major breakthrough, but there remains no uniform standard for predicting the efficacy of TKI therapy. AIMS: We retrospectively reviewed the use of EGFR-TKIs for advanced NSCLC between January 2009 and December 2017 in a hospital, which 169 patients who treated with first-line TKIs were enrolled. SUBJECTS AND METHODS: Multiple clinical factors, including histology, age, and sex, were analyzed. We calculated the tumor shrinkage rate (TSR) by measuring the longest diameters of the main mass by computed tomography (CT) before TKI therapy and the first CT after TKI therapy. We evaluated overall survival (OS) and progression-free survival (PFS) after first-line TKI therapy, and we assessed factors predicting survival using the Kaplan-Meier method. RESULTS: Eligible patients were sorted into higher (n = 83) and lower (n = 86) TSR groups according to the mean TSR of 0.49%. The 83 patients with a higher TSR had longer PFS and OS than those in the 86 patients with a lower TSR (14.83 vs. 8.40 months, P < 0.001, and 31.03 vs. 20.10 months, P < 0.001, respectively). Multivariate analyses revealed that TSR was an independent predictor of PFS and OS (PFS hazard ratio [HR]: 0.506, P < 0.001, and OS HR: 0.291, P < 0.001). CONCLUSIONS: These cumulative data support that TSR may be an early predictor of the treatment efficacy in NSCLC with EGFR mutations treated with first-line TKIs.

LncRNA PRNCR1 interacts with HEY2 to abolish miR-448-mediated growth inhibition in non-small cell lung cancer.

It has been announced in accumulative studies that non-coding (nc)RNAs are responsible for a varieties of biological behaviors during the progression of tumors. As two subgroups of ncRNAs family, micro (mi)RNAs can interact with long non-coding (lnc)RNAs, thereby forming ceRNA network. In this study, miR-448 was expressed higher in NSCLC tissues (P < 0.01) and NSCLC cell lines (P < 0.01). Moreover, low expression of miR-448 predicted poor prognosis for patients with NSCLC (P < 0.001). Functional assays revealed the anti-oncogenic function of miR-448 in NSCLC by inhibiting cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT). Mechanically, miR-448 was found to be negatively regulated by lncRNA PRNCR1 (prostate cancer non-coding RNA 1). Moreover, HEY2 (Hairy and enhancer of split-related with YRPW motif protein 2) was demonstrated to be the target mRNA of miR-448 in NSCLC cells. All mechanism experiments revealed that lncRNA PRNCR1 exerted ceRNA function in NSCLC by regulating miR-448 and HEY2. To validate the function of PRNCR1-miR-488-HEY2 network in NSCLC progression, rescue assays were conducted. Taken all together, we confirmed that lncRNA PRNCR1 upregulates HEY2 to promote tumor progression in NSCLC by competitively binding miR-448.

PRMT7 contributes to the metastasis phenotype in human non-small-cell lung cancer cells possibly through the interaction with HSPA5 and EEF2.

BACKGROUND: Non-small-cell lung cancer (NSCLC) constitutes the leading cause of cancer death in humans. Previous studies revealed the essential role of the protein arginine methyltransferase 7 (PRMT7) in promoting metastasis in breast cancer. However, its function and potential mechanism in NSCLC remain unclear. MATERIALS AND METHODS: The gene expression of PRMT7 between lung cancer tissues and normal tissues was studied with online database (http://medicalgenome.kribb.re.kr/GENT/). NSCLC cell lines with specific gene overexpression were constructed with lentivirus transduction. Matrigel invasion and colony formation assays were performed to evaluate the invasion and colony formation abilities. Co-immunoprecipitation coupled with mass spectrometry analysis was performed to explore the potential interaction proteins of PRMT7. Bioinformatic analysis was performed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. RESULTS: Online analysis of gene expression patterns revealed the relatively high expression of PRMT7 in lung cancer tissues. PRMT7 overexpression was able to promote the invasion and colony formation of A549 and SPC-A1 cells. A total of 19 in-common proteins shared by both NSCLC cell lines were identified to be interacting with PRMT7 and found to participate in a wide variety of pathways and protein-protein interactions according to bioinformatic analysis. Among them, HSPA5 and EEF2 were further investigated for their essential roles in PRMT7-promoted NSCLC cell invasion. CONCLUSION: Our results suggested PRMT7 overexpression was able to promote metastasis in NSCLC possibly through the interaction with HSPA5 and EEF2, which provides the potential mechanism of oncogenesis in lung cancer.

Molecular Mechanism Behind the Resistance of the G1202R-Mutated Anaplastic Lymphoma Kinase to the Approved Drug Ceritinib.

Anaplastic lymphoma kinase (ALK) has been regarded as an essential target for the treatment of nonsmall cell lung cancer (NSCLC). However, the emergence of the G1202R solvent front mutation that confers resistance to the drugs was reported for the first as well as the second generation ALK inhibitors. It was thought that the G1202R solvent front mutation might hinder the drug binding. In this study, a different fact could be clarified by multiple molecular modeling methodologies through a structural analogue of ceritinib (compound 10, Cpd-10) that is reported to be a potent inhibitor against the G1202R mutation. Herein, molecular docking, accelerated molecular dynamics (aMD) simulations in conjunction with principal component analysis (PCA), and free energy map calculations were used to produce reasonable and representative initial conformations for the conventional MD simulations. Compared with Cpd-10, the binding specificity of ceritinib between ALK wild-type (ALKWT) and ALK G1202R (ALKG1202R) are primarily controlled by the conformational change of the P-loop- and A-loop-induced energetic redistributions, and the variation is nonpolar interactions, as indicated by conventional MD simulations, PCA, dynamic cross-correlation map (DCCM) analysis, and free energy calculations. Furthermore, the umbrella sampling (US) simulations were carried out to make clear the principle of the dissociation processes of ceritinib and Cpd-10 toward ALKWT and ALKG1202R. The calculation results suggest that Cpd-10 has similar dissociation processes from both ALKWT and ALKG1202R, but ceritinib is more easily dissociated from ALKG1202R than from ALKWT, thus less residence time is responsible for the ceritinib resistance. Our results suggest that both the binding specificity and the drug residence time should be emphasized in rational drug design to overcome the G1202R solvent front mutation of ALK resistance.

Design, synthesis, anti-lung cancer activity, and chemosensitization of tumor-selective MCACs based on ROS-mediated JNK pathway activation and NF-κB pathway inhibition.

EF24 and F35 both were effective monocarbonyl curcumin analogues (MCACs) with excellent anti-tumor activity, however, drug defect such as toxicity may limit their further development. To get anti-lung cancer drugs with high efficiency, low toxicity and chemosensitization, a series of analogues based on EF24 and F35 were designed and synthesized. A number of compounds were found to exhibit cytotoxic activities selectively towards lung cancer cells compared to normal cells. Among these compounds, 5B was considered as an optimal anti-tumor agent for lung cancer cells with IC50 values ranging from 1.0 to 1.7 µM, selectivity index (SI, as a logarithm of a ratio of IC50 value for normal and cancer cells) were all above 1.1, while the SI of EF24 and F35 were less than 0.8. Consistent with selectivity in vitro, 5B was observed to show lower toxicity in acute toxicity experiment than EF24 and F35 respectively. Further, 5B was found to exert anti-tumor effects through ROS-mediated activation of JNK pathway and inhibition of NF-κB pathway. 5B could significantly enhance the sensitivity of A549 cells to cisplatin or 5-Fu. These findings suggested that 5B was an effective and less toxic MCAC and provided a promising candidate for anti-tumor drugs.

MiR-760 enhances TRAIL sensitivity in non-small cell lung cancer via targeting the protein FOXA1.

Non-small cell lung cancer (NSCLC) is one of the leading cause of death worldwide. TNF-related apoptosis-inducing ligand (TRAIL) is a promising anti-tumor agent with the ability to kill tumor cells while spare normal ones. MicroRNAs (miRNAs) are small, non-coding RNAs that play vital roles in carcinogenesis. Although miR-760 has been reported to be dysregulated in a variety of cancers, the role of miR-760 in NSCLC is not fully understood, and the relationship between miR-760 dysregulation and TRAIL sensitivity is still elusive. In the current study, we found that miR-760 is significantly downregulated in NSCLC tissues and cell lines. We also found that ectopic expression of miR-760, by targeting the FOXA1, enhanced TRAIL sensitivity in NSCLC cells. Correspondingly, silencing of FOXA1 also sensitized NSCLC cell to TRAIL-induced apoptosis and proliferation inhibition. In summary, these findings suggest that miR-760 should be considered as a tumor suppressor since it negatively regulates the oncogene protein FOXA1 and regulated TRAIL sensitivity in NSCLC cells.

Surgical resection of pulmonary metastases from colorectal cancer: 11 years of experiences.

OBJECTIVE: To analyze the benefits and prognostic factors after surgical resection of pulmonary metastases from colorectal cancer (CRC). METHODS: From Jan. 2004 to Jan. 2015, continuous 88 cases diagnosed with pulmonary metastases from CRC, including 15 cases of synchronous metastases and 73 metachronous metastases, were analyzed in the retrospective study. RESULTS: All of these 88 cases underwent curative pulmonary resection including 8 cases of simultaneous surgery. The one-year, three-year and five-year survival of the 88 cases were 93.4%, 60.2% and 35.7%, respectively. 63 patients just have one metastasis, and 25 patients have more than one metastasis. Additionally, the one-year, three-year and five-year survival was 98.1%, 70.2% and 40.3% respectively in one metastasis group, while 80.1%, 37.9% and 22.5% respectively in more than one metastasis group (p = 0.003). DFS of 37 metachronous metastases were equal or greater than 18 months, and DFS of 36 metachronous metastases were less than 18 months. The one-year, three-year and five-year survival was 97.8%, 77.9% and 41.4% respectively in the DFS≥18 month group, while 88.2%, 44.6% and 28.1% respectively in the DFS<18 month group (p = 0.01). CONCLUSION: Surgical resection of pulmonary metastases from colorectal cancer can improve survival rate in selected patients. It seems that the number of metastases is an independence prognostic factor in surgical treatment. Furthermore, longer DFI implies longer survival for resectable CRC pulmonary metastases.

Reduction of atrial fibrillation by Tanshinone IIA in chronic heart failure.

The aim of the present study was to confirm the effect of Tanshinone IIA (TAN) on the prevention of AF in chronic heart failure (CHF), and to elucidate the underlying electrophysiological mechanisms for the antiarrhythmic effects of TAN at the level of the atrium in an experimental model of CHF. In 10 female rabbits, CHF was induced by rapid ventricular pacing, leading to a significant decrease in ejection fraction in the presence of a dilated left ventricle and atrial enlargement. Twelve rabbits were sham-operated and served as controls. Isolated hearts were perfused using the Langendorff method. Burst pacing was used to induce AF. Monophasic action potential recordings showed an increase of atrial action potential duration (aAPD) and effective refractory period (aERP) in CHF hearts compared with sham hearts. Infusion of acetylcholine (1µm) and isoproterenol (1µm) led to AF in all failing hearts and in 11 sham hearts. Simultaneous infusion of TAN (10µm) remarkably reduced inducibility of AF in 50% of sham and 50% of failing hearts. TAN had no effect on aAPD but significantly increased aERP, leading to a marked increase in atrial post-repolarization refractoriness. Moreover, TAN application moderately increased interatrial conduction time. TAN has been shown to be effective in reducing the inducibility of AF in an experimental model of AF. The antiarrhythmic effect is mainly due to prolongations of atrial post-repolarization refractoriness and a moderate increase in interatrial conduction time.

MicroRNA-451 sensitizes lung cancer cells to cisplatin through regulation of Mcl-1.

As one of the most widely used chemotherapy drugs for lung cancer, chemoresistance of cisplatin (DPP) is one of the major hindrances in treatment of this malignancy. The microRNAs (miRNAs) have been identified to mediate chemotherapy drug resistance. MiR-451 as a tumor suppressor has been evaluated its potential effect on the sensitivity of cancer cells to DDP. However, the role of miR-451 in regulatory mechanism of chemosensitivity in lung cancer cells is still largely unknown. In this study, we first constructed a cisplatin-resistant A549 cell line (A549/DPP) accompanied with a decreased expression of miR-451 and an increased expression of Mcl-1in the drug resistant cells compared with the parental cells. Exogenous expression of miR-451 level in A549/DPP was found to sensitize their reaction to the treatment of cisplatin, which coincides with reduced expression of Mcl-1. Interestingly, Mcl-1 knockdown in A549/DPP cells increased the chemosensitivity to DPP, suggesting the dependence of Mcl-1 regulation in miR-451 activity. Moreover, miR-451 can restore cisplatin treatment response in cisplatin-resistant xenografts in vivo, while Mcl-1 protein levels were decreased. Thus, these findings provided that in lung cancer cells, tumor suppressor miR-451 enhanced DPP sensitivity via regulation of Mcl-1 expression, which could be served as a novel therapeutic target for the treatment of chemotherapy resistant in lung cancer.