SIAH2-Mediated Degradation of ACSL4 Inhibits the Anti-Tumor Activity of CD8+ T Cells in Hepatocellular Carcinoma.

SIAH2 function as an oncogene in various cancer. However, the roles of SIAH2 in hepatocellular carcinoma (HCC) are still unknown. This study aimed to investigate the roles of SIAH2 in HCC. Immunohistochemistry was used determine SIAH2 and ACSL4 expression in clinical samples. RT-qPCR was used to determine mRNA expression. Western blot assay was applied for determining protein expression. Ubiquitination assay was conducted for determining ubiquitination of ACSL4. Xenograft experiment was applied for determining tumor growth. Flow cytometry was applied to determine the functions of CD4+ and CD8+ T cells. SIAH2 expression was overexpressed in HCC tumors. High levels of SIAH2 predicted poor outcomes. However, SIAH2 knockdown promoted the proliferation of CD8+ T cells as well as promoted the ferroptosis of tumor cells, inhibiting tumor growth in HCC. ACSL4 is required for CD8+ T cell-mediated ferroptosis of HCC cells. However, SIAH2 induced ubiquitination of ACSL4 and inhibited its expression. SIAH2 specific inhibitor menadione promoted the immune checkpoint blockade. Taken together, SIAH2-mediated inactivation of CD8+ T cells inhibits the ferroptosis of HCC via mediating ubiquitination of ACSL4. Therefore, targeting SIAH2 may be a promising strategy for HCC.

HOMER3 promotes liver hepatocellular carcinoma cancer progression by -upregulating EZH2 and mediating miR-361/GPNMB axis.

Liver hepatocellular carcinoma (LIHC) is among the most lethal human cancers. Studies have shown that Homer scaffold protein 3 (HOMER3) plays important roles in various diseases and cancers, but its biological function and molecular mechanism in LIHC have never been investigated. Our study discovered the aberrantly high expression of HOMER3 and its promising diagnostic and prognostic significance in LIHC. Functionally, HOMER3 knockdown inhibited the proliferative and migrative abilities of LIHC cells and tumor growth in vivo. Mechanically, HOMER3 mediated the aggressiveness of LIHC cells via GPNMB. Meanwhile, miR-361 directly targeted GPNMB and attenuated LIHC progression by suppressing GPNMB expression. The regulatory effect of HOMER3 during LIHC progression was exerted through the miR-361/GPNMB axis. Furthermore, EZH2 supplementation or miR-361 depletion effectively abated the tumor-suppressive effect of HOMER3 knockdown on LIHC progression. In conclusion, HOMER3 mediated LIHC progression through the EZH2/miR-361/GPNMB axis.

Smart PROTACs Enable Controllable Protein Degradation for Precision Cancer Therapy.

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional chemicals that degrade proteins at the post-translational level, which represent an emerging therapeutic modality to fight cancer and other diseases. Although several PROTACs have now entered clinical trials, potential off-tissue side effects have resulted from nonspecific accumulation at non-cancerous sites after systemic administration, and this remains a major challenge. To this end, in the past 3 years, activatable PROTACs whose activity can only be launched on demand have gained tremendous momentum. In this review, we provide an overview of these new smart activatable PROTACs, which exert protein degradation action only in response to internal or external stimuli. We categorize these activatable PROTACs according to their activation mechanism contributed by different stimuli, including reduction-activatable, hypoxia-activatable, and enzyme-activatable PROTACs and photo-caged or photo-switchable PROTACs. The use of stimuli-responsive chemical blocks in these activatable PROTACs allows local activation of the antitumor effects while reducing the incidence of off-site side effects for precision cancer therapy. The design principle and category of smart PROTACs are introduced along with an overview of their therapeutic prospects and challenges.

UCK2 regulated by miR-139-3p regulates the progression of hepatocellular carcinoma cells.

Objective: This study mainly explores how UCK2 impacts the progression of hepatocellular carcinoma (HCC). Methods: Mature miRNA and mRNA expression data along with the clinical data of HCC were provided by The Cancer Genome Atlas to mine differentially expressed miRNAs and mRNAs. Expression levels of UCK2 and miR-139-3p in HCC were tested through quantitative real-time PCR. How UCK2 and miR-139-3p impacted HCC cell activities were detected by Transwell, wound healing and cell proliferation approaches. Whether miR-139-3p could bind to UCK2 was detected by dual-luciferase assay. Results: This investigation found evidently high levels of UCK2 in both HCC tissue and cells and its marked association with poor prognosis. Overexpression of UCK2 could significantly promote the behaviors of HCC cells. In addition, poorly expressed miR-139-3p was inversely associated with UCK2. Dual-luciferase method also proved the association. The rescue experiment showed that miR-139-3p regulated cell behaviors in HCC through targeting UCK2. Conclusion: Highly expressed UCK2 was mediated by miR-139-3p to modulate cell behaviors in HCC. It is assumed that UCK2 is a possible target of HCC for cancer therapy purposes.

Globally, a large number of patients succumb to hepatocellular carcinoma (HCC) each year. Only 10­37% patients can undergo surgery because of hepatic failure and advanced tumors. Though the recovery rate after excision is 20­30%, the 5-year survival rate is low, and postoperative recurrence rate is high. Despite the widespread application of HCC screening, only few patients in the early stage have been diagnosed. Hence, it is urgent to explore its potential mechanism. This study investigates the relationship between aberrant expression of mRNA and malignancy of HCC cells. Finally, the abnormally high expression of UCK2 is correlated with patients' low survival rate and poor prognosis.

miR-221-3p regulates hepatocellular carcinoma cell proliferation, migration and invasion via targeting LIFR.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the most common and fatal cancers in the world. This study aims to investigate the mechanism by which miR-221-3p regulates HCC cell proliferation, migration and invasion, so as to provide a new idea for targeted therapy towards HCC. MATERIALS AND METHODS: Expression quantification data including mature miRNA and mRNA were accessed from TCGA-LIHC dataset, and matched clinical information was obtained as well, which helped identify the miRNA of interest. Thereafter, effect of the miRNA on HCC cell biological functions was assessed with a series of in vitro experiments, such as qRT-PCR, MTT, wound healing assay and Transwell. To gain more insight into the mechanism of the miRNA in HCC, bioinformatics method was conducted to predict downstream target gene. The potential targeting relationship between the miRNA and the predicted mRNA was validated by dual-luciferase reporter assay. Western blot was performed to test protein expression. RESULTS: MiR-221-3p identified by differential expression analysis was found to be significantly elevated in HCC tissue. Overexpressing miR-221-3p noticeably enhanced HCC cell proliferative, migratory and invasive abilities. Leukemia inhibitory factor receptor (LIFR), confirmed as a downstream target of miR-221-3p in HCC by dual-luciferase reporter assay, was poorly expressed in HCC tissue and cells. Additionally, the expression of LIFR was decreased following the targeted binding between miR-221-3p and LIFR 3'-UTR, while increasing the expression of LIFR attenuated the promoting effect of miR-221-3p on HCC cells. CONCLUSION: MiR-221-3p is an oncogene in HCC cells, and it exerts its role in HCC cell viability and motility via targeting LIFR.

Drugging the "undruggable" microRNAs.

As a naturally occurring class of gene regulators, microRNAs (miRNAs) have attracted much attention as promising targets for therapeutic development. However, RNAs including miRNAs have long been considered undruggable, and most efforts have been devoted to using synthetic oligonucleotides to regulate miRNAs. Encouragingly, recent findings have revealed that miRNAs can also be drugged with small molecules that directly target miRNAs. In this review paper, we give a summary of recently emerged small-molecule inhibitors (SMIs) and small-molecule degraders (SMDs) for miRNAs. SMIs are small molecules that directly bind to miRNAs to inhibit their biogenesis, and SMDs are bifunctional small molecules that upon binding to miRNAs induce miRNA degradation. Strategies for discovering SMIs and developing SMDs were summarized. Applications of SMIs and SMDs in miRNA inhibition and cancer therapy were also introduced. Overall, SMIs and SMDs introduced here have high potency and specificity in miRNA inhibition. We envision that these small molecules will pave the way for developing novel therapeutics toward miRNAs that were previously considered undruggable.

Small molecules with big roles in microRNA chemical biology and microRNA-targeted therapeutics.

MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression. Aberrant miRNA expression or function have close links with various human diseases. Therefore, therapeutic treatments with disease-associated miRNAs as targets are emerging. However, the intracellular miRNA networks are extremely complicated and poorly understood, which thus hinder the development of miRNA-targeted therapeutics. Small molecules that are able to regulate endogenous miRNAs hold great potential in both elucidation of miRNA networks and treatment of miRNA-related diseases. Herein, we summarize current strategies for discovery of small molecule modifiers of miRNAs, and we highlight aspects of miRNA cellular biology elucidated by using these small molecules and miRNA-targeted therapeutics realized by these small molecules. We envision that this area will expand dramatically in the near future and will ultimately contribute to a better understanding of miRNA-involved cellular processes and development of therapeutic agents for miRNA-associated diseases.

LncRNA­AB209371 promotes the epithelial­mesenchymal transition of hepatocellular carcinoma cells.

The zinc finger protein Snail1 is an important factor in the regulation of the epithelial­mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) cells. The present study demonstrated that the expression of Snail1 in HCC tissues was significantly higher compared with its expression in tissues adjacent to primary sites, as determined via western blotting. Furthermore, the results of a dual luciferase assay revealed that hsa­microRNA(miR)199a­5p negatively regulated the protein expression of Snail1 by binding to its 3' untranslated region. However, in a comparative analysis of primary HCC and its metastatic tissues using reverse transcription­quantitative polymerase chain reaction and western blotting, it was demonstrated that the expression of hsa­miR199a­5p and Snail1 in HCC metastatic tissues were significantly higher compared with primary lesions and an association between them identified that hsa­miR199a­5p lost its ability to negatively regulate Snail1. This result is contradictive to the fact that hsa­miR199a­5p inhibits the expression of the Snail1 protein. The present study hypothesized that the aberrant expression of long non­coding RNA was the cause of hsa­miR199a­5p inactivation based on loss of function rather than a reduction in content. The data collected in the present study confirmed the hypothesis that AB209371 binds to hsa­miR199a­5p and weakened the inhibitory effect of hsa­miR199a­5p on Snail1 expression. In addition, an in vitro EMT model was established in the present study by inducing HCC cells with TGF­ß1. The results revealed that AB209371 silencing effectively reversed the hsa­miR199a­5p mediated inhibition of EMT by negatively regulating Snail1 protein expression. Therefore, AB209371 silencing in combination with hsa­miR199a­5p expression may serve as an effective means to inhibit EMT in HCC cells. The present study also revealed that hsa­miR199a­5p/Snail1 exhibits a dominant regulatory effect in the EMT of HCC cells via a Snail1 recovery experiment. In conclusion, to the best of our knowledge, the present study confirmed for the first time that the high expression of AB209371 is favorable for the EMT in HCC cells and may be a direct cause of hsa­miR199a­5p inactivation (an HCC metastasis suppressor). Additionally, AB209371 silencing combined with hsa­miR199a­5p overexpression may be an effective means to inhibit the metastasis of HCC and the EMT of HCC cells.

Two-stage versus single-stage procedure for the management of cholecystocholedocholithiasis in elderly patients: a retrospectively cohort study

Background: there is an increasing incidence rate of cholecysto-choledocholithiasis associated with the increasing proportion of senile individuals. Methods: a total of 100 elderly patients (over 80 years of age) suffering both from cholelithiasis and choledocholithiasis were retrospectively studied from January 2010 to December 2016. Patients were scheduled for either a single-stage or two-stage procedure. The LCBDE group (n = 54) included cases that underwent a single stage procedure of laparoscopic exploration of the common bile duct combined with cholecystectomy. The ERCP/EST group (n = 46) included cases that underwent a two stage procedure of preoperative endoscopic retrograde cholangiopancreaticography with endoscopic sphincterotomy followed by cholecystectomy. Comorbidity conditions, presenting symptoms, bile duct clearance, length of hospital stay and the frequency of procedural, postoperative and long-term complications were recorded. Results: the LCBDE group had a higher stones clearance rate than the ERCP/EST group (100.0% vs 89.1%, p < 0.05). Postoperative complications and hospitalization length were comparable in the two groups (p > 0.05). There were more procedural complications in the ERCP/EST group than in the LCBDE group (10.8% vs 0%, p < 0.05). Furthermore, a patient in the ERCP/EST group died due to duodenal perforation. More patients in the ERCP/EST group experienced long-term complications than those in the LCBDE group (23.9% vs 3.7%, p < 0.05) during a mean follow-up period of 28.4 months. Conclusions: the single-stage procedure is a safe and effective technique for elderly patients with cholecysto-choledocholithiasis. LCBDE provides a good stone clearance rate with few long term complications

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LncRNA-H19 activates CDC42/PAK1 pathway to promote cell proliferation, migration and invasion by targeting miR-15b in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the main causes of cancer-related death. This study aims to explore the role and underlying mechanism of H19 in HCC. METHODS: qRT-PCR detected miR-15b-5p and H19 expression, as well as the mRNA level of EMT-associated genes. Western blotting detected protein level of EMT-associated genes. Immunohistochemistry (IHC) examined CDC42 in HCC tissues. Dual luciferase reporter assay verified the regulatory mechanism among H19, miR-15b and CDC42. Colony formation, wound healing assay, transwell, flow cytometry measured proliferation, migration, invasion and apoptosis, respectively. RESULTS: H19 and CDC42 were up-regulated while miR-15b was down-regulated in HCC cells and tissues. miR-15b interacted with H19 and CDC42 3'-UTR. H19 knockdown inhibited proliferation, migration and invasion, and increased apoptosis, which was rescued by miR-15b inhibitor. H19 knockdown suppressed CDC42/PAK1 pathway and EMT progress. CONCLUSION: H19 knockdown inhibited proliferation, migration and invasion, and promoted apoptosis of HCC cells via targeting miR-15b/CDC42/PAK1 axis.

Two-stage versus single-stage procedure for the management of cholecystocholedocholithiasis in elderly patients: a retrospectively cohort study.

BACKGROUND: there is an increasing incidence rate of cholecysto-choledocholithiasis associated with the increasing proportion of senile individuals. METHODS: a total of 100 elderly patients (over 80 years of age) suffering both from cholelithiasis and choledocholithiasis were retrospectively studied from January 2010 to December 2016. Patients were scheduled for either a single-stage or two-stage procedure. The LCBDE group (n = 54) included cases that underwent a single stage procedure of laparoscopic exploration of the common bile duct combined with cholecystectomy. The ERCP/EST group (n = 46) included cases that underwent a two stage procedure of preoperative endoscopic retrograde cholangiopancreaticography with endoscopic sphincterotomy followed by cholecystectomy. Comorbidity conditions, presenting symptoms, bile duct clearance, length of hospital stay and the frequency of procedural, postoperative and long-term complications were recorded. RESULTS: the LCBDE group had a higher stones clearance rate than the ERCP/EST group (100.0% vs 89.1%, p < 0.05). Postoperative complications and hospitalization length were comparable in the two groups (p > 0.05). There were more procedural complications in the ERCP/EST group than in the LCBDE group (10.8% vs 0%, p < 0.05). Furthermore, a patient in the ERCP/EST group died due to duodenal perforation. More patients in the ERCP/EST group experienced long-term complications than those in the LCBDE group (23.9% vs 3.7%, p < 0.05) during a mean follow-up period of 28.4 months. CONCLUSIONS: the single-stage procedure is a safe and effective technique for elderly patients with cholecysto-choledocholithiasis. LCBDE provides a good stone clearance rate with few long term complications.

MicroRNAs as novel endogenous targets for regulation and therapeutic treatments.

MicroRNAs (miRNAs) are small non-coding RNAs that have been identified as key endogenous biomolecules that are able to regulate gene expression at the post-transcriptional level. The abnormal expression or function of miRNAs has been demonstrated to be closely related to the occurrence or development of various human diseases, including cancers. Regulation of these abnormal miRNAs thus holds great promise for therapeutic treatments. In this review, we summarize exogenous molecules that are able to regulate endogenous miRNAs, including small molecule regulators of miRNAs and synthetic oligonucleotides. Strategies for screening small molecule regulators of miRNAs and recently reported small molecules are introduced and summarized. Synthetic oligonucleotides including antisense miRNA oligonucleotides and miRNA mimics, as well as delivery systems for these synthetic oligonucleotides to enter cells, that regulate endogenous miRNAs are also summarized. In addition, we discuss recent applications of these small molecules and synthetic oligonucleotides in therapeutic treatments. Overall, this review aims to provide a brief synopsis of recent achievements of using both small molecule regulators and synthetic oligonucleotides to regulate endogenous miRNAs and achieve therapeutic outcomes. We envision that these regulators of endogenous miRNAs will ultimately contribute to the development of new therapies in the future.

Biliary exploration via the left hepatic duct orifice versus the common bile duct in left-sided hepatolithiasis patients with a history of biliary tract surgery: A randomized controlled trial.

BACKGROUND: Hepatectomy and additional common bile duct exploration are required for the treatment of left-sided hepatolithiasis (LSH). METHODS: Eligible LSH patients (n = 62) scheduled for open left lateral segmentectomy or left hemihepatectomy with intraoperative biliary exploration via the left hepatic duct orifice (LHD group, n = 35) or the common bile duct (CBD group, n = 27) were retrospectively studied. T-tube insertion was performed on selected patients. Primary outcome measures included overall operative time, length of hospital stay, intraoperative complications, residual stones, and postoperative bile leaks. RESULTS: There were no residual stones observed in the 2 groups. Ten patients in the CBD group received T-tube placement, whereas no patients in the LHD group received T-tube placement. There were more patients in the CBD group suffered intraoperative complications and postoperative bile leakage than LHD group (P < .05). The LHD group had a significantly shorter operative time and hospitalization than the CBD group (P < .05). CONCLUSION: For left-sided hepatolithiasis patients with a history of biliary tract surgery, LHD cholangioscopy is an accessible technique that simplifies the operation procedure by avoiding choledochotomy and subsequent T-tube insertion, which results in lower complication rates as well as shorter operative duration and length of hospitalization.

MicroRNA­302a inhibits cell proliferation and invasion, and induces cell apoptosis in hepatocellular carcinoma by directly targeting VEGFA.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer­related mortality worldwide. An increasing number of studies have demonstrated that microRNAs may be used as diagnostic, therapeutic and prognostic targets for human cancers, including HCC. The present study aimed to evaluate microRNA (miR)­302a expression and function in HCC, and its underlying mechanisms. The results revealed that miR­302a was expressed at low levels in HCC tissues and cell lines. Reduced miR­302a expression was correlated with tumor­node­metastasis stage and lymph node metastasis in patients with HCC. Additionally, overexpression of miR­302a reduced cell proliferation and invasion, and induced apoptosis in HCC cells. Vascular endothelial growth factor A (VEGFA) was demonstrated to be a direct target gene of miR­302a. VEGFA was highly expressed in HCC tissues and inversely correlated with miR­302a expression. Knockdown of VEGFA expression led to reduced HCC cell proliferation and invasion, and increased apoptosis rates, similar to miR­302a overexpression, which suggested that VEGFA may be a functional downstream target of miR­302a in HCC. These data suggested that this newly identified miR­302a/VEGFA axis may be involved in HCC formation and progression. The present results also provide novel potential targets for the treatments of patients with HCC.

Three modalities on common bile duct exploration.

Background Choledocholithiasis can be managed by transcystic (TC) and transduct (TD) stone extraction or using cholangioscopy through the left hepatic duct orifice (LHD). Objective The aim of this study is to evaluate the safety and effectiveness of common bile duct exploration through the TC approach, TD approach, and LHD approach for choledocholithiasis, with a specific emphasis on the TC and LHD approaches versus the TD approach. Methods Between January 2011 and June 2014, a total of 172 choledocholithiasis patients accompanied by cholecystitis and/or left intrahepatic gallstones were scheduled for laparoscopic or open common bile duct (CBD) exploration using cholangioscopy through the CBD (TD group: n = 72), cystic duct (TC group: n = 63), or LHD orifice (LHD group: n = 37). T-tube insertion was performed in selected patients. Patients were regularly followed up at bimonthly intervals or more frequently in presence of any symptom. Primary outcomes measures included overall operative time, length of hospital stay, and postoperative bile leaks. Results Successful bile duct clearance was 100 % in the TD group, 93.6 % in the TC group, and 90.9 % in the LHD group. Sixteen cases in the TD group had T-tube placement in contrast to no cases in the TC and LHD groups. There were more bile leaks after TD stone extraction (12.5 %) than TC (3.2 %) and LHD stone extraction (0 %), which prolonged hospitalization in the TD group more than in the TC and LHD groups. For choledocholithiasis patients accompanied by cholecystitis, 2 groups (TC and TD groups) were comparable in operative time. However, for choledocholithiasis patients accompanied by left intrahepatic gallstones, the LHD group had a significantly shorter operative time than the TD group (121.1 ±â€Š16.9 minutes vs. 149.3 ±â€Š42.8 minutes, p < 0.05). Conclusion The TD group had a higher stone clearance rate but was associated with a higher risk of bile leaks. TC and LHD stone extraction, which seems to be the more effective approach with lower complication rates, is an accessible technique that simplifies the operation procedure by avoiding choledochotomy and subsequent T-tube insertion.

Three modalities on management of choledocholithiasis: A prospective cohort study.

BACKGROUND: Choledocholithiasis can be managed by endoscopic retrograde cholangiopancreaticography/endoscopic sphincterotomy (ERCP/EST) or laparoscopic common bile duct (CBD) exploration by transcystic (TC) or transductal (TD) stone extraction. OBJECTIVE: The aim of this study was to evaluate the safety and effectiveness of common bile duct stones extraction by ERCP/EST, TC approach and TD approach for choledocholithiasis, with specific emphasis on ERCP/EST, TC approach versus TD approach. METHODS: Between January 2011 and June 2014, a total of 161 patients were scheduled for two-stage (preoperative ERCP/EST followed by cholecystectomy, ERCP group, n = 52)or single-stage (laparoscopic exploration of the CBD combined with cholecystectomy, n = 109) treatment for choledocholithiasis with concomitant cholecystitis. Laparoscopic common bile duct exploration was performed by TC approach (TC group, n = 63)or TD approach (TD group, n = 46). T-tube insertion was performed in selected patients. Patients were regularly followed up at bimonthly intervals or more frequently in presence of any symptom. Primary outcomes measures included length of hospital stay, successful bile duct clearance, postoperative/procedural morbidity and mortality. RESULTS: Successful bile duct clearance was 100.0% in TD group, 93.7% in TC group and 92.3% in ERCP group. 4 cases in the TC group and 4 cases in the ERCP group required an extra choledocholithotomy due to impacted stones. 9 patients underwent T-tube drainage in TD group comparing to 1 case in ERCP group and no cases in TC group. Comparing to TC group, there was more postoperative morbidity in TD and ERCP group. Bile leaks were more frequent in TD group (8.7%) than TC (3.2%) and ERCP group (3.8%), which prolonged hospitalization in TD group than TC and ERCP group. 2 patients in ERCP group suffered duodenal perforation and one of them died because of the complication. However, total procedural morbidity was 0% in TC and TD group. CONCLUSION: TD stone extraction has a higher stone clearance but with a higher risk of bile leaks. Procedural morbidity is more often happened in ERCP/EST, which may result in serious consequences. TC stone extraction, which seems an effective approach with lower complication rates, is accessible techniques simplifying the operation procedure by avoiding choledocholithotomy and subsequent T-tube insertion.

Mesoporous Silica Nanoparticles as Carriers for Intracellular Delivery of Nucleic Acids and Subsequent Therapeutic Applications.

Nucleic acids, including DNA, microRNA (miRNA), small interfering RNA (siRNA), and antisense oligonucleotide (ASO), are powerful gene regulators, which have been demonstrated as promising drug candidates for therapeutic treatments. Nevertheless, poor cellular membrane permeability and serum stability have greatly hindered the applications of nucleic acids in biomedicine. To address these issues, associate carriers that can encapsulate and protect nucleic acids are urgently required. Mesoporous silica nanoparticles (MSNs or MSNPs), which are nanomaterials with excellent biocompatibility, large surface area for functionalization, and tunable pore size for encapsulating different cargos, are emerging as novel and ideal biomaterials for different biomedical applications. In this review paper, we focus on the applications of MSNs in nucleic acid delivery and nucleic acid-guided therapeutic treatments. General strategies for the preparation of nucleic acid-MSN complexes will be firstly introduced, followed by a summary of recent applications of MSNs in nucleic acid delivery and nucleic acid-guided therapeutics.

Increased phosphorylation of 4E­binding protein 1 predicts poor prognosis for patients with colorectal cancer.

As demonstrated in previous studies, the phosphorylated form of 4E­binding protein 1 (p­4E­BP1) may be a suitable tumor biomarker. The aim of the current study was to examine the expression status of p­4E­BP1 in colorectal cancer (CRC), in order to determine its clinical significance. The present study enrolled 89 patients with CRC that had undergone radical resection. Paired tumor and adjacent normal tissues were evaluated using immunohistochemistry to detect the protein expression of p­4E­BP1 and phosphatase and tensin homolog (PTEN). The study identified 53 cases (59.6%) that exhibited moderate or high expression of p­4E­BP1 in tumor tissues, compared with little or no expression in the adjacent normal tissues. Conversely, PTEN protein expression was markedly lower in CRC compared with adjacent normal tissues. p­4E­BP1 protein upregulation tissues samples was consistent with PTEN downregulation in CRC samples. p­4E­BP1 overexpression was predominant in patients with metastasis to the regional lymph nodes. Moderate/high expression of p­4E­BP1 protein was significantly associated with adverse overall survival (OS) in patients. Statistical analysis using the Cox proportional hazards model, indicated that p­4E­BP1 expression was an independent factor suitable for predicting OS in CRC patients, which was independent of lymph node metastasis. In conclusion, p­4E­BP1 protein expression appears to be upregulated in CRC, suggesting that it may be a suitable biomarker for predicting CRC prognosis.

Clinical Significance of Long Non-coding RNA MALAT1 Expression in Tissue and Serum of Breast Cancer.

Long non-coding RNAs (lncRNAs) have been proven to serve a critical role in cancer development and progression. The aim of this study was to elucidate clinical significance of lncRNA MALAT1 expression in breast cancer (BC). A total of 78 BC patients treated with radical resection were enrolled in this study. Quantitative reverse transcription-polymerase chain reaction was used to detect MALAT1 expression in tissues and serum samples. The receiver operating characteristics (ROC) curve was constructed to describe diagnostic specificity and sensitivity. Lentivirus-mediated RNA interference was used to knockdown MALAT1 in the MDA-MB-231 cell line, and then cell proliferation and invasion were explored. Results showed that MALAT1 expression was significantly up-regulated in 85.9% (67/78) of cancerous tissues compared with normal counterparts (P<0.01). Further, an elevated MALAT1 expression in BC tissue was significantly associated with lymph metastasis (P=0.037) and adverse 5-year disease-free survival (mean 48.5 months vs 62.7 months, P=0.012). Suppression of lncRNA MALAT1 significantly inhibited BC cells proliferation, migration and invasion, induced apoptosis and cell cycle G1 arrest. In addition, serum MALAT1 levels in BC patients were much higher than levels in patients with benign breast disease (P<0.001), its diagnostic efficacy was satisfactory, area under the curve (AUC) was 0.833. In conclusion, MALAT1 upregulation plays an important rolein BC development, and serum MALAT1 level may be a potential tumor marker for BC diagnosis.