Chaperone-mediated autophagy degrade Dicer to promote breast cancer metastasis.

Metastasis in breast cancer usually lead to the majority of deaths on clinical patients. Accordingly, diagnosis of metastasis at the early stage in breast cancer is important to improve the prognosis. We observed that Dicer protein levels are significant decrease in highly invasive breast cancer cells and usually correlated with poor clinical outcomes. Following, we aim to clarify the molecular regulatory mechanism of this phenomenon in breast cancer to provide a new therapeutic target. In this study, we obtained that Dicer expression correlated with metastasis and invasion without affect cell stability in breast cancer cells. Importantly, we identified the regulatory mechanism of Dicer protein degradation, the chaperone-mediated autophagy (CMA)-mediated degradation that is major mechanism to decrease Dicer protein expression and lead to cancer metastasis. We discovered that heat shock cognate 71-kDa protein (Hsc70) which as a CMA-related factor interacts with the CMA-targeting motif I333A/K334A on Dicer to promote degradation through CMA. Taken together, our findings hint that Dicer highly correlated with cancer metastasis, we reveal the tumor-promoting effect of CMA-mediated Dicer degradation in breast cancer.

Novel heavily fucosylated glycans as a promising therapeutic target in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is highly prevalent and lethal globally, and its prognosis remains unsatisfactory. Drug resistance is regarded as the main cause of treatment failure leading to tumor recurrence and metastasis. The overexpression of fucosylated epitopes, which are usually modifications of glycoproteins, was reported to occur in various epithelial cancers. However, the effects of treatments that target these antigens in colorectal cancer remain unclear. METHODS: This study investigated the expression of heavily fucosylated glycans (HFGs) in 30 clinical samples from patients with CRC and other normal human tissues. The complement-dependent cytotoxicity was explored in vitro through treatment with anti-HFG monoclonal antibody (mAb) alone or in combination with chemotherapeutic agents. In vivo inhibitory effects were also examined using a xenograft mouse model. RESULTS: Immunohistochemistry staining and western blotting revealed that HFG expression was higher in human colorectal cancer tissues than in normal tissues. In DLD-1 and SW1116 cells, which overexpress fucosylated epitopes, anti-HFG mAb produced observable cytotoxic effects, especially when it was combined with chemotherapeutic agents. The xenograft model also demonstrated that anti-HFG mAb had potent and dose-dependent inhibitory effects on colorectal tumor growth. CONCLUSIONS: As a novel cancer antigen, HFGs are a promising treatment target, and the implementation of anti-HFG mAb treatment for CRC warrants further investigation.

Spin-Polarized Photocatalytic CO2 Reduction of Mn-Doped Perovskite Nanoplates.

"Spin" has been recently reported as an important degree of electronic freedom to improve the performance of electrocatalysts and photocatalysts. This work demonstrates the manipulations of spin-polarized electrons in CsPbBr3 halide perovskite nanoplates (NPLs) to boost the photocatalytic CO2 reduction reaction (CO2RR) efficiencies by doping manganese cations (Mn2+) and applying an external magnetic field. Mn-doped CsPbBr3 (Mn-CsPbBr3) NPLs exhibit an outstanding photocatalytic CO2RR compared to pristine CsPbBr3 NPLs due to creating spin-polarized electrons after Mn doping. Notably, the photocatalytic CO2RR of Mn-CsPbBr3 NPLs is significantly enhanced by applying an external magnetic field. Mn-CsPbBr3 NPLs exhibit 5.7 times improved performance of photocatalytic CO2RR under a magnetic field of 300 mT with a permanent magnet compared to pristine CsPbBr3 NPLs. The corresponding mechanism is systematically investigated by magnetic circular dichroism spectroscopy, ultrafast transient absorption spectroscopy, and density functional theory simulation. The origin of enhanced photocatalytic CO2RR efficiencies of Mn-CsPbBr3 NPLs is due to the increased number of spin-polarized photoexcited carriers by synergistic doping of the magnetic elements and applying a magnetic field, resulting in prolonged carrier lifetime and suppressed charge recombination. Our result shows that manipulating spin-polarized electrons in photocatalytic semiconductors provides an effective strategy to boost photocatalytic CO2RR efficiencies.

Sweetening Lithium Metal Interface by High Surface and Adhesive Energy Coating of Crystalline α-d-Glucose Film to Inhibit Dendrite Growth.

The notorious growth of lithium (Li) dendrites and the instability of the solid electrolyte interface (SEI) during cycling make Li metal anodes unsuitable for use in commercial Li-ion batteries. Herein, the use of simple sugar coating (α-d-glucose) is demonstrated on top of Li metal to halt the growth of Li dendrites and stabilize the SEI. The α-d-glucose layer possesses high surface and adhesive energies toward Li, which promote the homogenous stripping and plating of Li ions on top of the Li metal. Density functional theory reveals that Li-ion diffusion within the α-d-glucose layer is governed by hopping around the bare sides of the O atoms and along the apparent passages formed by the glucose molecules. Stable cycling performance is achieved when combining α-d-glucose-coated Li (G|Li) anodes with sulfur- and LiFePO4 -based cathodes in both LiTFSI (ether) and LiPF6 (carbonate) electrolyte systems. A G|Li-based symmetrical cell operates at a current density of 1 mA cm-2 and areal capacity of 1 mAh cm-2 displays a stable overpotential profile for over 9 months (7000 h) of continuous charge/discharge cycling.

Routine intraoperative cholangiography during laparoscopic cholecystectomy: application of the 2016 WSES guidelines for predicting choledocholithiasis.

BACKGROUND: Routine use of intraoperative cholangiography (IOC) during laparoscopic cholecystectomy (LC) for detecting common bile duct stones remains controversial. The 2016 World Society of Emergency Surgery (WSES) guidelines on acute calculous cholecystitis proposed a risk stratification for choledocholithiasis. Our present study aimed to (1) examine the findings of common bile duct (CBD) stones in patients underwent LC with routine use of IOC, and (2) validate the 2016 WSES risk classes for predicting choledocholithiasis. METHODS: All patients had LC with IOC routinely performed from November 2012 to December 2017 were reviewed retrospectively. Patients were classified into high-, intermediate-, and low-risk groups based on the 2016 WSES risk classes with modification. RESULTS: A total of 990 patients with LC and routine IOC were enrolled. CBD stones were detected in 197 (19.9%) patients. The rate of CBD stone detected in low-, intermediate-, high-risk groups were 0%, 14.2%, and 89.6%, respectively. Predictors as following: evidence of CBD stones on abdominal ultrasound or computed tomography, CBD diameter > 6 mm, total bilirubin > 4 mg/dL, bilirubin level = 1.8-4 mg/dL, abnormal liver biochemical test result other than bilirubin, presence of clinical gallstone pancreatitis had statistical significance between patients with and without CBD stones. Major bile duct injury was found in 4 patients (0.4%). All 4 patients had uneventful recovery after repair surgery. CONCLUSIONS: Based on our study results, the 2016 WSES risk classes for choledocholithiasis could be an effective approach for predicting the risk of choledocholithiasis. Considering its advantages for detecting CBD stones and biliary injuries, the routine use of IOC is still suggested.

Inter-rater and intra-rater reliability of the current assessment model and tools for laparoscopic suturing.

BACKGROUND: Moorthy checklist (MC) and laparoscopic skill competency assessment tool (LS-CAT) are tools commonly used to evaluate the quality of laparoscopic suturing. The current assessment model is single measurement by multiple raters. Our aim is to examine the reliability of the current assessment model and tools. METHODS: With IRB approval, participants of three different backgrounds, namely medical students, trainees, and surgeons, were enrolled. The participants each accomplished a standardized laparoscopic suturing task. The performances were video-recorded and reviewed with LS-CAT and MC independently by three blinded raters. Intraclass correlation coefficients (ICC) were calculated for inter-rater and intra-rater reliability. RESULTS: 26 participants were enrolled, comprising 10 students, 10 trainees and 6 surgeons. In regard of inter-rater reliability, ICC values (95% CI) were 0.909 (0.768-0.961) and 0.868 (0.608-0.948) in LS-CAP and MC, respectively. For students, ICC values were 0.908 (0.682-0.976) and 0.815 (0.408-0.951) in LS-CAT and MC, respectively. For trainees, ICC values were 0.812 (0.426-0.947) and 0.717 (0.102-0.925), respectively. For surgeons, ICC values were 0.720 (0.064-0.955) and 0.868 (0.608-0.948), respectively. In regard of intra-rater reliability, ICC values of the mean scores from the three raters were 0.956 (0.905-0.980) and 0.925 (0.842-0.966) in LS-CAP and MC, respectively. CONCLUSION: LS-CAT and MC are both qualified assessment tools for laparoscopic suturing. LS-CAT is more reliable particularly for medical students and trainees. The current assessment model of single measurement by multiple raters provides excellent reliability.

ERK-mediated transcriptional activation of Dicer is involved in gemcitabine resistance of pancreatic cancer.

Gemcitabine has been a commonly used therapeutic agent for treatment of pancreatic cancer. In the clinic, a growing resistance to gemcitabine has been observed in patients with pancreatic cancer, and investigation of the underlying mechanism of gemcitabine resistance is urgently required. The microRNA (miRNA)-producing enzyme, Dicer, is crucial for the maturation of miRNAs, and is involved in clinical aggressiveness, poor prognosis, and survival outcomes in various cancers, however, the role of Dicer in acquired gemcitabine resistance of pancreatic cancer is still not clear. Here, we found that Dicer expression was significantly increased in gemcitabine-resistant PANC-1 (PANC-1/GEM) cells compared with parental PANC-1 cells and observed a high level of Dicer correlated with increased risk of pancreatic cancer. Suppression of Dicer obviously decreased gemcitabine resistance in PANC-1/GEM cells; consistently, overexpression of Dicer in PANC-1 cells increased gemcitabine resistance. Moreover, we identified that transcriptional factor Sp1 targeted the promoter region of Dicer and found ERK/Sp1 signaling regulated Dicer expression in PANC-1/GEM cells, as well as positively correlated with pancreatic cancer progression and suggest that targeting the ERK/Sp1/Dicer pathway has potential therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

Laser-assisted LED for adaptive-driving-beam headlights employing ultra-reliable single crystal phosphor for autonomous vehicles.

A novel laser-assisted LED for adaptive-driving-beam (ADB) headlights employing an ultra-reliable Ce3+: YAG-based single crystal phosphor (SCP)-converter layer for use in autonomous vehicles is demonstrated. The SCP fabricated at a high-temperature of 1,940°C exhibited better thermal stability than other phosphor-converter materials, evidenced by a thermal aging test. The high-beam pattern of the ADB is measured at a luminous intensity of 88,436 cd at 0°, 69,393 cd at ± 2.5°, and 42,942 cd at ± 5°, which well satisfies the ECE R112 class B regulation. The advantage of introducing the laser-assisted LED system employing the highly reliable SCP is to produce the high intensity for the ADB, which enables the increase of the field of view by 20% and the brightness by 28% for the ADB headlight and results in improving the visibility from ± 7° to ± 8.5° and the illumination distance up to 200 m. This proposed advance ADB headlight with the ultra-reliable SCP and the novel laser-assisted LED is favorable as one of the most promising ADB light source candidates for use in the next-generation autonomous vehicle applications.

AXL is crucial for E1A-enhanced therapeutic efficiency of EGFR tyrosine kinase inhibitors through NFI in breast cancer.

AXL which is a chemosensitizer protein for breast cancer cells in response to epidermal growth factor receptor-tyrosine kinase inhibitor and suppresses tumor growth. The clinical information show nuclear factor I (NFI)-C and NFI-X expression correlate with AXL expression in breast cancer patients. Following, we establish serial deletions of AXL promoter to identify regions required for Adenovirus-5 early region 1A (E1A)-mediated AXL suppression. All of the NFI family members were extensively studied for their expression and functions in regulating AXL. Moreover, E1A post-transcriptionally downregulates AXL expression through NFI. NFI-C and NFI-X, not NFI-A and NFI-B, resulting in cell death in response to EGFR-TKI. Our finding suggests that NFI-C and NFI-X are crucial regulators for AXL and significantly correlated with poor survival of breast cancer patients.

Long-term and short-term surgical outcomes of single-incision laparoscopic hepatectomy on anterolateral liver segments.

BACKGROUND: Laparoscopic liver resection yields improved short-term surgical outcomes, whereas the reports about clinical benefits of single-incision laparoscopic hepatectomy (SILH) are scarce. This retrospective study is to compare the surgical outcomes of SILH with those of multi-incision laparoscopic hepatectomy (MILH). METHODS: The study included 54 patients who had undergone SILH and 184 patients who had undergone MILH between January 2010 and December 2017. Short-term outcomes were compared in those of patients who underwent left lateral sectionectomy and partial hepatectomy of segment 5-6. A subgroup analysis of hepatocellular carcinoma (HCC) was also performed for long-term outcome comparisons. RESULTS: In those of patients who underwent left lateral sectionectomy, SILH group had less chronic hepatitis B (15.2 vs. 45.8%; p = 0.004), less liver cirrhosis (12.1 vs. 50.0%; p = 0.002), less tumor proximal to major vessel (6.1 vs. 29.2%; p = 0.018), shorter surgical time (113.2 ± 37.9 vs. 146.0 ± 50.5 min; p = 0.007), and shorter postoperative hospital stays (4.4 ± 1.1 vs. 5.4 ± 1.3 days; p = 0.002) compared with MILH group. In those of patients with tumor located at segment 5-6, no significant differences were observed in surgical time, blood loss, complications, and mortality. Single-incision laparoscopic partial hepatectomy was only associated with wider surgical margins (11.8 ± 7.0 vs. 5.3 ± 5.2 mm; p = 0.003). In the HCC subgroup, SILH had similar 1-, 3-, and 5-year overall survival and 1-, 3-, and 5-year recurrence-free survival rates compared with patients who had undergone MILH. CONCLUSIONS: The study demonstrates the safety and feasibility of single-incision laparoscopic liver resection for left lateral sectionectomy and partial hepatectomy for segment 5-6. In selected patients within the group and by experienced surgical team, the SILH technique results in comparable short-term surgical outcomes and long-term oncological outcomes.

An advanced laser headlight module employing highly reliable glass phosphor.

An advanced laser headlight module (LHM) employing highly reliable glass phosphor is demonstrated. The novel glass-based YAG phosphor-converter layers fabricated by low-temperature of 750°C exhibited better thermal stability. The LHM consisted of a 5 × 1 blue laser diode array, an aspherical lens, a glass phosphor-converter layer with an aluminum thermal dissipation substrate, and a dichroic filter to allow pass blue light and reflect yellow phosphor light. The 5 × 1 blue laser array was packaged with five blue lasers having optical power of 1.2 W per laser. The LHM exhibited total output optical power of 6 W, luminous flux of 1860 lm, relative color temperature of 4100 K, and efficiency of more than 310 lm/W. The high-beam patterns of the LHMs were measured to be 45,000 luminous intensity (cd) at 0°, 31,000 cd at ± 2.5°, and 12,500 cd at ± 5°, which were well satisfied the ECE R112 class B regulation. The proposed high-performance LHM with highly reliable glass-based phosphor-converter layer fabricated by low temperature is favorable as one of the promising LHM candidates for use in the next-generation automobile headlight applications.

Long-term and short-term surgical outcomes of laparoscopic versus open liver resection for hepatocellular carcinoma: might laparoscopic approach be better in early HCC?

BACKGROUND: This retrospective study compared the short- and long-term outcomes of laparoscopic liver resection (LLR) and open liver resection (OLR) and identified patients who might gain more benefits from LLR. METHODS: The demographic and perioperative data, short-term surgical outcomes, and long-term oncological results of all 313 patients who received elective liver resection for hepatocellular carcinoma (HCC) between January 2010 and June 2017 were analyzed. The patients were then divided into stage-specific subgroups according to the TNM staging system for comparison. RESULTS: LLR was performed in 153 patients and OLR in 160 patients. LLR is associated with less blood loss (p < 0.001), shorter surgical time (p = 0.001), shorter length of hospital stay (p < 0.001), and lower morbidity rate (p = 0.034). The 5-year overall survival (OS) rates in the LLR group were higher than those in the OLR group (78.1 vs. 57.6%; p = 0.002). Stage-specific subgroup analysis revealed similar 5-year OS in the two groups (stage I: 82.8 vs. 82.6%, p = 0.845; stage II: 80.3 vs. 69.2%, p = 0.638; stage III: 55.6 vs. 34.8%, p = 0.681), as did the 5-year recurrence-free survival. Moreover, the short-term outcomes were better in the LLR group in terms of surgical time, blood loss, and length of hospital stay, and these benefits attenuated with advancing tumor stage. CONCLUSIONS: LLR for HCC is a safe and feasible procedure that does not compromise long-term oncological outcomes. In early tumor stages, LLR might be better in terms of short-term surgical outcomes.

Risk Factors Analysis of Postoperative Pleural Effusion after Liver Resection.

BACKGROUND: Pulmonary complications remain relatively high in morbidities that arise after liver surgery and are associated with increased length of hospital stay and higher cost. Identification of possible risk factors in this retrospective analysis may help reduce operative morbidity and achieve better outcomes. METHODS: In all, 363 consecutive patients underwent elective hepatectomies between July 2008 and November 2013 and these were identified and analyzed retrospectively. Patient demographics and perioperative variables were collected. The main outcome was an analysis of risk factors associated with postoperative pleural effusion (PPE). RESULTS: Of 363 patients receiving hepatectomies, 80 patients (22.0%) developed pulmonary complications. The predominant pulmonary complication in this series is pleural effusion (76 patients, 95%). Univariate analysis found that older age, higher body mass index (BMI), chronic obstructive lung disease, asthma, heart disease, hepatitis C infection, heavy smoking, American Society of Anesthesiology class III and IV, hepatectomy site, combined surgeries, perioperative blood transfusion, and cirrhosis of liver were associated with PPE. Only older age, higher BMI, asthma, heavy smoker, combined gastrointestinal surgeries, and perioperative blood transfusion were identified as independent risk factors in multivariate analysis. CONCLUSION: This study identifies 6 risk factors for PPE. Identification and management of some of these factors could possibly reduce morbidity and improve short-term surgical outcomes.

Prophylactic Central Neck Dissection for Papillary Thyroid Carcinoma with Clinically Uninvolved Central Neck Lymph Nodes: A Systematic Review and Meta-analysis.

BACKGROUND: Central neck dissection and total thyroidectomy are standard treatments for patients with papillary thyroid carcinoma (PTC) with clinically involved central nodes. However, prophylactic central neck dissection (pCND) in patients with clinically uninvolved cN0 has been beneficial in some studies but ineffective in others. We conducted a meta-analysis to evaluate the efficacy and safety of pCND in patients with central neck lymph nodes cN0 PTC. METHODS: The PubMed, EMBASE, Cochrane Library, and Scopus databases and the ClinicalTrials.gov registry were electronically searched for studies published until September 2017. The meta-analysis was conducted to calculate the pooled effect size by using random-effects model. Treatment efficacies were measured by determining locoregional recurrence (LRR). Secondary outcomes included transient recurrent laryngeal nerve (RLN) injury, permanent RLN injury, transient hypocalcemia, and permanent hypocalcemia. RESULTS: Twenty-three retrospective and prospective cohort studies involving 18,376 patients were reviewed. Patients who underwent pCND had significantly lower LRR (odds ratio [OR] 0.65; 95% confidence interval [CI] 0.48-0.88) but significantly higher incidence rates of transient RLN injury (OR 2.03; 95% CI 1.32-3.13), transient hypocalcemia (OR 2.23; 95% CI 1.84-2.70), and permanent hypocalcemia (OR 2.22; 95% CI 1.58-3.13) than that of no pCND group. CONCLUSION: Compared with no pCND, pCND significantly reduces LRR but is accompanied by numerous adverse effects. The clinical decision should be made after the shared decision-making process of clinicians and patients.

Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma.

Angiopoietin-like protein 1 (ANGPTL1) has been shown to act as a tumor suppressor by inhibiting angiogenesis, cancer invasion, and metastasis. However, little is known about the effects of ANGPTL1 on sorafenib resistance and cancer stem cell properties in hepatocellular carcinoma (HCC) and the mechanism underlying these effects. Here, we show that ANGPTL1 expression positively correlates with sorafenib sensitivity in HCC cells and human HCC tissues. ANGPTL1 significantly decreases epithelial-mesenchymal transition (EMT)-driven sorafenib resistance, cancer stemness, and tumor growth of HCC cells by repressing Slug expression. ANGPTL1 directly interacts with and inactivates MET receptor, which contributes to Slug suppression through inhibition of the extracellular receptor kinase/protein kinase B (ERK/AKT)-dependent early growth response protein 1 (Egr-1) pathway. ANGPTL1 expression inversely correlates with Slug expression, poor sorafenib responsiveness, and poor clinical outcomes in HCC patients. CONCLUSION: ANGPTL1 inhibits sorafenib resistance and cancer stemness in HCC cells by repressing EMT through inhibition of the MET receptor-AKT/ERK-Egr-1-Slug signaling cascade. ANGPTL1 may serve as a novel MET receptor inhibitor for advanced HCC therapy. (Hepatology 2016;64:1637-1651).

Outcome Analysis of Patients with Gallstone Disease Receiving Cholecystectomy: A Population-Based Cohort Study.

BACKGROUND/AIMS: Cholecystectomy is generally performed to treat patients with gallstone disease (GSD) in clinical practice. The present study aimed to investigate whether type 2 diabetes mellitus (T2DM) may influence the overall survival of GSD patients. METHODS: The National Health Insurance Research Database, a population-based registry data in Taiwan, was used to identify GSD patients from 2001 to 2008. The risk of cancers and effects of T2DM on the overall survival of GSD patients receiving cholecystectomy were estimated by hazards ratios (HRs) and 95% CIs using the Cox proportional hazard model. RESULTS: Among 392,028 eligible GSD patients, 81,971 underwent cholecystectomy, whereas 310,057 did not. After cholecystectomy, the HR for developing cancer was 1.14. The HR for the overall survival was 0.74-fold lower for patients who underwent cholecystectomy than that for patients who did not. GSD patients without T2DM who underwent cholecystectomy (0.78-fold lower risk) had a longer survival, whereas those with T2DM had shorter survival (1.64-fold higher risk without cholecystectomy and 1.13-fold higher risk with cholecystectomy) compared with those without T2DM who did not undergo cholecystectomy. CONCLUSIONS: Our major findings suggest that T2DM may worsen the prognosis of GSD patients after cholecystectomy, which provides useful insight into the treatment of T2DM among GSD patients in clinical settings.

Highly active and stable hybrid catalyst of cobalt-doped FeS2 nanosheets-carbon nanotubes for hydrogen evolution reaction.

Hydrogen evolution reaction (HER) from water through electrocatalysis using cost-effective materials to replace precious Pt catalysts holds great promise for clean energy technologies. In this work we developed a highly active and stable catalyst containing Co doped earth abundant iron pyrite FeS(2) nanosheets hybridized with carbon nanotubes (Fe(1-x)CoxS(2)/CNT hybrid catalysts) for HER in acidic solutions. The pyrite phase of Fe(1-x)CoxS(2)/CNT was characterized by powder X-ray diffraction and absorption spectroscopy. Electrochemical measurements showed a low overpotential of ∼0.12 V at 20 mA/cm(2), small Tafel slope of ∼46 mV/decade, and long-term durability over 40 h of HER operation using bulk quantities of Fe(0.9)Co(0.1)S(2)/CNT hybrid catalysts at high loadings (∼7 mg/cm(2)). Density functional theory calculation revealed that the origin of high catalytic activity stemmed from a large reduction of the kinetic energy barrier of H atom adsorption on FeS(2) surface upon Co doping in the iron pyrite structure. It is also found that the high HER catalytic activity of Fe(0.9)Co(0.1)S(2) hinges on the hybridization with CNTs to impart strong heteroatomic interactions between CNT and Fe(0.9)Co(0.1)S(2). This work produces the most active HER catalyst based on iron pyrite, suggesting a scalable, low cost, and highly efficient catalyst for hydrogen generation.

E1A-mediated inhibition of HSPA5 suppresses cell migration and invasion in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is defined by reduced expression of the estrogen receptor, progesterone receptor, and HER2. TNBC is an especially aggressive group of breast cancers with poor prognosis. There are currently no validated molecular targets to effectively treat this disease. Thus, it is necessary to identify effective molecular targets and therapeutic strategies for TNBC patients. METHODS: The expression of HSPA5 in patients with breast cancer was examined by immunohistochemistry. The association of HSPA5 expression with tumor grade and metastatic events in TNBC patients was analyzed using the Oncomine database. The knockdown and overexpression of HSPA5 protein were performed to investigate the effects on E1A-suppressed cell migration/invasion of TNBC using in vitro transwell assays and tumor growth/experimental metastasis studies in animal models. RESULTS: The expression of HSPA5 was positively correlated with high-grade tumors, metastatic events, and poor overall survival in breast cancer patients with TNBC. E1A-inhibited HSPA5 expression suppressed cell migration/invasive ability of TNBC cell lines. Moreover, E1A significantly abolished lung metastases from breast cancer cells by inhibiting HSPA5 expression in a xenograft tumor model. CONCLUSIONS: The overexpression of HSPA5 is critical for high-risk metastasis of breast cancer and TNBC. The results of our study suggest that HSPA5 may be a crucial mediator of E1A-suppressed metastatic ability of breast cancer cells. Thus, E1A may be a potential target for diagnosis and individualized treatment in clinical practice.

Suppression of Dicer increases sensitivity to gefitinib in human lung cancer cells.

BACKGROUND: Accumulating evidence is revealing an important role of microRNA (miRNA) in tumor progression and chemotherapeutic resistance. Dicer is a cytoplasmic endoribonuclease type III crucial for production of mature miRNAs. The aberrant expression of Dicer has also been reportedly associated with clinical aggressiveness, prognosis, and patient survival in various cancer types. However, the molecular mechanisms of Dicer in acquired gefitinib resistance are still not clear. METHODS: In this study, we analyzed the protein level of Dicer between gefitinib-sensitive (PC9) and gefitinib-resistant (PC9/GR) non-small-cell lung cancer (NSCLC) cell lines by Western blot analysis. Silence and overexpression of the Dicer were performed to investigate the effects on gefitinib sensitivity, as assessed by (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay and sub-G1 assay of flow cytometry. To further explore the mechanism of chemoresistance, we examined whether Dicer knockdown led to modulating specific miRNAs and its miRNA target genes. RESULTS: Dicer expression was significantly increased in PC9/GR compared with PC9 cells. Knockdown of Dicer restores gefitinib sensitivity in resistant cells, and overexpression of Dicer enhances resistance to gefitinib in sensitive cells. Silencing of Dicer induces sensitivity to gefitinib in NSCLC cells through the downregulation of miR-30b/c and miR-221/222 to increase the protein level of caspase-3, resulting in an increase in gefitinib-induced apoptosis. CONCLUSIONS: Dicer contributes to the resistance to gefitinib in lung cancer. These results indicate that Dicer may be a target for diagnosis and therapy of patients with resistance to gefitinib.

Silencing survivin activates autophagy as an alternative survival pathway in HCC cells.

Autophagy is a survival mechanism that is activated in response to nutrient deprivation. The link between aberrant autophagy and cancer has been increasingly recognized. Survivin, an anti-apoptotic molecule, and the autophagy pathway are correlated with therapeutic responses to cancer. However, the role of autophagy in cancer progression remains unclear. Here, we generated survivin knockdown cells (survivin-KD) by introducing a short interfering RNA (siRNA) into hepatocellular carcinoma (HCC) cells, and we observed a 20 % reduction in the survival of these survivin-KD cells, as determined by MTT assay. In addition, an increased number of stress granules, increased positive staining by acridine orange and a shift in the high side scatter (SSC) cell population in flow cytometry analysis were observed in survivin-KD cells. Furthermore, electron microscopy revealed an increased number of autophagosomes in survivin-KD cells compared with scrambled control cells. Finally, we treated cells with an autophagy inhibitor, 3-MA, and observed a decrease in cell survival in survivin-KD cells compared with scrambled control cells. Our study suggests that an autophagy signal may be activated after the anti-apoptotic molecule survivin is suppressed. This finding implies that autophagy may be an alternative survival pathway in HCC cells and may provide a basis for the development of new therapeutic strategies for HCC.