Publications by authors named "Hangyu Li"

40 Publications

OCT3/4 enhances tumor immune response by upregulating the TET1-dependent NRF2/MDM2 axis in bladder cancer.

Genomics 2021 Apr 21. Epub 2021 Apr 21.

Department of General Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110000, PR China. Electronic address:

This study aimed to investigate the function of OCT3/4 on tumor immune escape in bladder cancer. Initially, the expression of OCT3/4, TET1, NRF2 and MDM2 was quantified in tumor tissues and cells, followed by gain- or loss-of-function studies to define their roles in cell migration, invasion and apoptosis and tumorigenicity in nude mice. Bladder cancer presented with abundant expression levels of OCT3/4, TET1, NRF2 and MDM2. We found that OCT3/4 promoted TET1 expression via binding to its promoter and that TET1 recruited MLL protein to NRF2 promoter and upregulated its expression, while NRF2 enhanced MDM2 expression. Upregulated MDM2 accelerated tumor immune escape in bladder cancer in mice. OCT3/4 knockdown suppressed the cell migration and invasion while inducing apoptosis, and consequently prevented tumor growth and immune escape in mice. Collectively, OCT3/4 may promote the progression of tumor immune escape in bladder cancer through acting as a promoter of the TET1/NRF2/MDM2 axis.
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http://dx.doi.org/10.1016/j.ygeno.2021.04.033DOI Listing
April 2021

Identifying Plant Pentatricopeptide Repeat Proteins Using a Variable Selection Method.

Front Plant Sci 2021 1;12:506681. Epub 2021 Mar 1.

College of Information and Computer Engineering, Northeast Forestry University, Harbin, China.

Pentatricopeptide repeat (PPR), which is a triangular pentapeptide repeat domain, plays an important role in plant growth. Features extracted from sequences are applicable to PPR protein identification using certain classification methods. However, which components of a multidimensional feature (namely variables) are more effective for protein discrimination has never been discussed. Therefore, we seek to select variables from a multidimensional feature for identifying PPR proteins. A framework of variable selection for identifying PPR proteins is proposed. Samples representing PPR positive proteins and negative ones are equally split into a training and a testing set. Variable importance is regarded as scores derived from an iteration of resampling, training, and scoring step on the training set. A model selection method based on Gaussian mixture model is applied to automatic choice of variables which are effective to identify PPR proteins. Measurements are used on the testing set to show the effectiveness of the selected variables. Certain variables other than the multidimensional feature they belong to do work for discrimination between PPR positive proteins and those negative ones. In addition, the content of methionine may play an important role in predicting PPR proteins.
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http://dx.doi.org/10.3389/fpls.2021.506681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957076PMC
March 2021

Emerging mechanisms and applications of ferroptosis in the treatment of resistant cancers.

Biomed Pharmacother 2020 Oct 17;130:110710. Epub 2020 Sep 17.

Department of General Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, Liaoning, China. Electronic address:

The development of chemotherapy drugs has promoted anticancer treatment, but the effect on tumours is not clear because of treatment resistance; thus, it is necessary to further understand the mechanism of cell death to explore new therapeutic targets. As a new type of programmed cell death, ferroptosis is increasingly being targeted in the treatment of many cancers with clinical drugs and experimental compounds. Ferroptosis is stimulated in tumours with inherently high levels of ferrous ions by a reaction with abundant polyunsaturated fatty acids and the inhibition of antioxidant enzymes, which can overcome treatment resistance in cancers mainly through GPX4. In this review, we focus on the intrinsic cellular regulators against ferroptosis in cancer resistance, such as GPX4, NRF2 and the thioredoxin system. We summarize the application of novel compounds and drugs to circumvent treatment resistance. We also introduce the application of nanoparticles for the treatment of resistant cancers. In conclusion, targeting ferroptosis represents a considerable strategy for resistant cancer treatment.
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http://dx.doi.org/10.1016/j.biopha.2020.110710DOI Listing
October 2020

Adaptively Learning Facial Expression Representation via C-F Labels and Distillation.

IEEE Trans Image Process 2021 21;30:2016-2028. Epub 2021 Jan 21.

Facial expression recognition is of significant importance in criminal investigation and digital entertainment. Under unconstrained conditions, existing expression datasets are highly class-imbalanced, and the similarity between expressions is high. Previous methods tend to improve the performance of facial expression recognition through deeper or wider network structures, resulting in increased storage and computing costs. In this paper, we propose a new adaptive supervised objective named AdaReg loss, re-weighting category importance coefficients to address this class imbalance and increasing the discrimination power of expression representations. Inspired by human beings' cognitive mode, an innovative coarse-fine (C-F) labels strategy is designed to guide the model from easy to difficult to classify highly similar representations. On this basis, we propose a novel training framework named the emotional education mechanism (EEM) to transfer knowledge, composed of a knowledgeable teacher network (KTN) and a self-taught student network (STSN). Specifically, KTN integrates the outputs of coarse and fine streams, learning expression representations from easy to difficult. Under the supervision of the pre-trained KTN and existing learning experience, STSN can maximize the potential performance and compress the original KTN. Extensive experiments on public benchmarks demonstrate that the proposed method achieves superior performance compared to current state-of-the-art frameworks with 88.07% on RAF-DB, 63.97% on AffectNet and 90.49% on FERPlus.
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http://dx.doi.org/10.1109/TIP.2021.3049955DOI Listing
January 2021

Chinese expert consensus on adult ventral abdominal wall defect repair and reconstruction.

Am J Surg 2020 Nov 17. Epub 2020 Nov 17.

Department of General Surgery, Huadong Hospital, Fudan University, Shanghai, 200040, China. Electronic address:

Background: Surgical management of patients with ventral abdominal wall defects, especially complex abdominal wall defects, remains a challenging problem for abdominal wall reconstructive surgeons. Effective surgical treatment requires appropriate preoperative assessment, surgical planning, and correct operative procedure in order to improve postoperative clinical outcomes and minimize complications. Although substantial advances have been made in surgical techniques and prosthetic technologies, there is still insufficient high-level evidence favoring a specific technique. Broad variability in existing practice patterns, including clinical pre-operative evaluation, surgical techniques and surgical procedure selection, are still common.

Data Sources: With the purpose of providing a best practice algorithm, a comprehensive search was conducted in Medline and PubMed. Sixty-four surgeons considered as experts on abdominal wall defect repair and reconstruction in China were solicited to develop a Chinese consensus and give recommendations to help surgeons standardize their techniques and improve clinical results.

Conclusions: This consensus serves as a starting point to provide recommendations for adult ventral abdominal wall repair and reconstruction in China and may help build opportunities for international cooperation to refine AWR practice.
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http://dx.doi.org/10.1016/j.amjsurg.2020.11.024DOI Listing
November 2020

Non-coding RNA derived from extracellular vesicles in cancer immune escape: Biological functions and potential clinical applications.

Cancer Lett 2021 Mar 10;501:234-246. Epub 2020 Nov 10.

Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China. Electronic address:

The tumor microenvironment represents a dynamically composed matrix into which cancer cells and many other cell types are embedded to form organ-like structures. The tumor immune microenvironment (TIME), composed of immune cells, is an inseparable part of the tumor microenvironment. Extracellular vesicles (EVs) participate in the occurrence and development of tumors by delivering various biologically active molecules between cells; their role in cancer immune escape in particular has been widely proven. EVs can carry a wide array of cargo, such as non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs, which are selectively loaded by EVs, secreted, and transported to participate in the proliferation of immune cells. Hence, strategies to specifically target EV-ncRNAs could be attractive therapeutic options. In this review, we summarize the current research on the role of EV-ncRNAs in cancer immune escape, and discuss the latest research on the function and regulation mechanism of EV-ncRNAs in cancer immune escape, highlighting and elucidating the potential clinical applications of EV-ncRNAs, including in diagnosis and immunotherapy.
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http://dx.doi.org/10.1016/j.canlet.2020.11.005DOI Listing
March 2021

IKKβ activation promotes amphisome formation and extracellular vesicle secretion in tumor cells.

Biochim Biophys Acta Mol Cell Res 2021 01 17;1868(1):118857. Epub 2020 Sep 17.

Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China. Electronic address:

Intracellular organelle cross-talk is a new and important research area. Under stress conditions, the coordinated action of the autophagy and endosomal systems in tumor cells is essential for maintaining cellular homeostasis and survival. The activation of the IκB kinase (IKK) complex is also involved in the regulation of stress and homeostasis in tumor cells. Here, we try to explore the effects of constitutively active IKKβ subunits (CA-IKKβ) on autophagy and endosomal system interactions. We confirm that CA-IKKβ induces accumulation of autophagosomes and their fusion with MVBs to form amphisomes in cancer cells, and also drives the release of EVs containing autophagy components through an amphisome-dependent mechanism. We further demonstrate that CA-IKKβ inhibits the expression of RAB7, thereby weakening the lysosomal-dependent degradation pathway. CA-IKKβ also induces phosphorylation of SNAP23 at Ser95 instead of Ser110, which further promotes amphisome-plasma membrane fusion and sEV secretion. These results indicate that CA-IKKβ drives the formation and transport of amphisomes, thereby regulating tumor cell homeostasis, which may illuminate a special survival mechanism in tumor cells under stress.
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http://dx.doi.org/10.1016/j.bbamcr.2020.118857DOI Listing
January 2021

Autonomous glucose metabolic reprogramming of tumour cells under hypoxia: opportunities for targeted therapy.

J Exp Clin Cancer Res 2020 Sep 14;39(1):185. Epub 2020 Sep 14.

Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.

Molecular oxygen (O) is a universal electron acceptor that is eventually synthesized into ATP in the mitochondrial respiratory chain of all metazoans. Therefore, hypoxia biology has become an organizational principle of cell evolution, metabolism and pathology. Hypoxia-inducible factor (HIF) mediates tumour cells to produce a series of glucose metabolism adaptations including the regulation of glucose catabolism, glycogen metabolism and the biological oxidation of glucose to hypoxia. Since HIF can regulate the energy metabolism of cancer cells and promote the survival of cancer cells, targeting HIF or HIF mediated metabolic enzymes may become one of the potential treatment methods for cancer. In this review, we summarize the established and recently discovered autonomous molecular mechanisms that can induce cell reprogramming of hypoxic glucose metabolism in tumors and explore opportunities for targeted therapy.
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http://dx.doi.org/10.1186/s13046-020-01698-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491117PMC
September 2020

Focus on the morphogenesis, fate and the role in tumor progression of multivesicular bodies.

Cell Commun Signal 2020 08 8;18(1):122. Epub 2020 Aug 8.

Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.

Multivesicular bodies (MVBs) are endosome organelles that are gradually attracting research attention. Initially, MVBs were considered as important components of the endosomal-lysosomal degradation pathway. In recent years, with an increase in extracellular vesicle (EV) research, the biogenesis, fate, and pathological effects of MVBs have been increasingly studied. However, the mechanisms by which MVBs are sorted to the lysosome and plasma membrane remain unclear. In addition, whether the trafficking of MVBs can determine whether exosomes are released from cells, the factors are involved in cargo loading and regulating the fate of MVBs, and the roles that MVBs play in the development of disease are unknown. Consequently, this review focuses on the mechanism of MVB biogenesis, intraluminal vesicle formation, sorting of different cargoes, and regulation of their fate. We also discuss the mechanisms of emerging amphisome-dependent secretion and degradation. In addition, we highlight the contributions of MVBs to the heterogeneity of EVs, and their important roles in cancer. Thus, we attempt to unravel the various functions of MVBs in the cell and their multiple roles in tumor progression. Video Abstract.
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http://dx.doi.org/10.1186/s12964-020-00619-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414566PMC
August 2020

Current prevalence of perioperative early venous thromboembolism and risk factors in Chinese adult patients with inguinal hernia (CHAT-1).

Sci Rep 2020 07 29;10(1):12667. Epub 2020 Jul 29.

Beijing Institute of Respiratory Diseases, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100043, China.

Venous thromboembolism (VTE) is an important postoperative complication. We investigated and analyzed the current inguinal hernia treatment methods and occurrence of early postoperative VTE in Chinese adults. This study involved data for patients with inguinal hernia hospitalized in 58 general hospitals in mainland China from January 1st, 2017 to December 31st, 2017. Data were retrospectively analyzed using a questionnaire. After data inputting and cleaning, we stratified and statistically analyzed patients' data using Caprini scores to create a high-, middle-, and low-risk group. A total of 14,322 patients with inguinal hernia were admitted to the 58 participating hospitals. After data collation and cleaning, 13,886 patients (97.0%) met our inclusion and exclusion criteria. The percentages of laparoscopic surgery and open surgery were 51.2% and 48.8%, respectively. 16 VTEs occurred during the hospitalization, accounting for 0.1% of all adverse events (95% confidence interval (CI) 0.11-0.13). The incidence of VTE was 0.2% (95% CI 0.18-0.2) in the high-risk group and 0.02% (95% CI 0.01-0.03) in the middle-risk group, based on Caprini scoring, with a significant difference (p < 0.0001). No VTE occurred in the low-risk group. Only 3,250 (23.4%) patients underwent Caprini risk assessment regarding treatment, with 13.2% receiving any prevention and only 1.2% receiving appropriate prevention. The treatment of inguinal hernia in Chinese adults has progressed somewhat; however, the evaluation and prevention of perioperative VTE was seriously neglected, in our study, and the incidence of postoperative VTE was underestimated postoperatively. Risk factors continue to be inadequately considered.
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http://dx.doi.org/10.1038/s41598-020-69453-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391649PMC
July 2020

YAP1 Inhibition in HUVECs Is Associated with Released Exosomes and Increased Hepatocarcinoma Invasion and Metastasis.

Mol Ther Nucleic Acids 2020 Sep 21;21:86-97. Epub 2020 May 21.

Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China. Electronic address:

Hepatocellular carcinoma is one of the most common gastrointestinal malignancies. Anti-angiogenesis therapies have recently demonstrated promise in the treatment of malignancies, although early treatment benefits may be accompanied by metastasis over time. Additional and more effective anti-angiogenic treatment modalities are therefore needed. We previously found that Yes-associated protein 1 (YAP1) expression is increased in hepatocellular carcinoma (HCC), particularly around tumor-associated blood vessels, suggesting a role in angiogenesis. The YAP1 inhibitor verteporfin is presently in anti-angiogenic clinical trials for the treatment of various cancers. Depleted YAP1 from vascular endothelial cells effectively reduced proliferation and tube formation, validating its utility as an anti-angiogenesis target. We also showed that YAP1 depletion or inhibition in vascular endothelial cells leads to increased release of exosomes containing the long non-coding RNA (lncRNA) MALAT1 into the tumor microenvironment. Direct exosomal transfer of MALAT1 to hepatic cells leads to increased hepatic cell invasion and migration via activation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. These observations may explain the occurrence of distant tumor metastasis with YAP1-associated anti-angiogenic therapy over time. It provides insight into new pathways and treatment paradigms that may be targeted to increase the long-term success of anti-angiogenic therapies.
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http://dx.doi.org/10.1016/j.omtn.2020.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281784PMC
September 2020

Removal of pharmaceuticals by fouled forward osmosis membranes: Impact of DOM fractions, Ca and real water.

Sci Total Environ 2020 Oct 29;738:139757. Epub 2020 May 29.

State Key Laboratory of Water Environment Simulation, School of Environment, Beijing Normal University, Beijing 100875, China; Xi'an High-Tech Institute, Xi'an 710025, China.

This study systematically investigated the impact of dissolved organic matters (DOM) fractions, Ca, membrane orientation and real water matrix on the membrane fouling and the subsequent pharmaceutical retention in forward osmosis (FO). Ca increased the removal of carbamazepine (CBZ) through steric effect, while it reduced sulfamethoxazole (SMZ) removal due to reduced electrostatic repulsion and enhanced external concentration polarization for three organic foulants. The study of operating mode showed that the pharmaceutical removal in pressure retarded osmosis (PRO) mode were lower than those in FO mode for both the baseline and HA fouling, which was attributed to the concentrative internal concentration polarization caused by long-term accumulation of pharmaceuticals or HA in support layer. In terms of the real water tests, the secondary effluent used as feed solution caused higher hydrophilicity and negative charge of fouled FO membrane, leading to increased removal of pharmaceuticals. Seawater used as draw solution also caused severe fouling in the support layer of FO with humic acid-like material as major foulants, increasing the removal of SMZ because of enhanced steric hindrance and electrostatic repulsion. However, the combined effects of increased adsorption and steric effect resulted in little change for the CBZ removal. This study gave implications on the practical application of FO process for pharmaceutical removal.
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http://dx.doi.org/10.1016/j.scitotenv.2020.139757DOI Listing
October 2020

MicroRNA-375 Targets ATG14 to Inhibit Autophagy and Sensitize Hepatocellular Carcinoma Cells to Sorafenib.

Onco Targets Ther 2020 28;13:3557-3570. Epub 2020 Apr 28.

Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang 110000, People's Republic of China.

Purpose: Sorafenib has revolutionized treatment of hepatocellular carcinoma (HCC), but its efficacy is limited by drug resistance. Autophagy is the process by which cellular components are transported to lysosomes for degradation, which promotes energy production and production of macromolecular precursors. Studies have suggested that the cytoprotective function of autophagy may contribute to chemoresistance or targeted drug resistance in cancer cells. We investigated the effects of miR-375 and autophagy-related protein 14, and their interrelationships, on sorafenib efficacy.

Methods: Cell viability was measured using the MTT assay, and apoptosis was evaluated using flow cytometry. Colony formation assay was performed to determine changes in cell number. Real-time PCR and Western blotting were performed to quantify the expression of key genes and proteins. Immunofluorescence and transmission electron microscopy were used to detect autophagy. Dual-luciferase reporter assays were used to verify a direct target.

Results: We characterized the relationship between sorafenib and autophagy. We showed that inhibition of autophagy enhanced sensitivity of HCC to sorafenib and showed that miR-375 was important in this process. Finally, we showed that miR-375 affected sensitivity of HCC cells to sorafenib through regulation of ATG14.

Conclusion: We showed that miR-375 sensitized HCC cells to sorafenib by blocking sorafenib-induced autophagy. We also showed that ATG14 was a direct autophagy-related target of miR-375. These findings indicated that miR-375-ATG14 was important in the development of sorafenib resistance in HCC.
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http://dx.doi.org/10.2147/OTT.S247655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197942PMC
April 2020

ECFS-DEA: an ensemble classifier-based feature selection for differential expression analysis on expression profiles.

BMC Bioinformatics 2020 Feb 5;21(1):43. Epub 2020 Feb 5.

College of Information and Computer Engineering, Northeast Forestry University, No.26 Hexing Road, Harbin, 150040, China.

Background: Various methods for differential expression analysis have been widely used to identify features which best distinguish between different categories of samples. Multiple hypothesis testing may leave out explanatory features, each of which may be composed of individually insignificant variables. Multivariate hypothesis testing holds a non-mainstream position, considering the large computation overhead of large-scale matrix operation. Random forest provides a classification strategy for calculation of variable importance. However, it may be unsuitable for different distributions of samples.

Results: Based on the thought of using an ensemble classifier, we develop a feature selection tool for differential expression analysis on expression profiles (i.e., ECFS-DEA for short). Considering the differences in sample distribution, a graphical user interface is designed to allow the selection of different base classifiers. Inspired by random forest, a common measure which is applicable to any base classifier is proposed for calculation of variable importance. After an interactive selection of a feature on sorted individual variables, a projection heatmap is presented using k-means clustering. ROC curve is also provided, both of which can intuitively demonstrate the effectiveness of the selected feature.

Conclusions: Feature selection through ensemble classifiers helps to select important variables and thus is applicable for different sample distributions. Experiments on simulation and realistic data demonstrate the effectiveness of ECFS-DEA for differential expression analysis on expression profiles. The software is available at http://bio-nefu.com/resource/ecfs-dea.
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http://dx.doi.org/10.1186/s12859-020-3388-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003361PMC
February 2020

LncRNA NEAT1 promotes autophagy via regulating miR-204/ATG3 and enhanced cell resistance to sorafenib in hepatocellular carcinoma.

J Cell Physiol 2020 04 23;235(4):3402-3413. Epub 2019 Sep 23.

Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, China.

Long noncoding RNAs (lncRNAs) has been acknowledged in tumorigenesis gradually because of the great importance in different cancers. LncRNA nuclear enriched abundant transcript 1 (NEAT1) is a novel lncRNA and has been reported to promote multiple cancer progression. However, the biological roles of NEAT1 in hepatocellular carcinoma (HCC) is not cleared nowadays. In the present research, the level of NEAT1 was found to be upregulated in HCC by The Cancer Genome Atlas. In addition, NEAT1 expression is negatively correlated with the survival rate in HCC. Further investigation revealed that NEAT1 upregulation inhibited sorafenib efficacy and promoted autophagy. We found that NEAT1 could be a sponge for microRNA-204 (miR-204) and inhibits its level to upregulate ATG3 expression. In addition to the above, we demonstrated that miR-204 mimics also attenuated tumor autophagy. And rescue assays demonstrated that NEAT1 promotes HCC autophagy through modulating miR-204/ATG3 pathway. Collectively, this study first demonstrated that a novel NEAT1/miR-204/ATG3 signaling regulates HCC progression.
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http://dx.doi.org/10.1002/jcp.29230DOI Listing
April 2020

Autophagy: A novel mechanism of chemoresistance in cancers.

Biomed Pharmacother 2019 Nov 9;119:109415. Epub 2019 Sep 9.

Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110000, PR China. Electronic address:

The success of targeted drug therapy for cancer patients has attracted extensive attention from academia and society. However, the rapid development of acquired drug resistance is becoming a major challenge. Autophagy, as an essential homeostatic and catabolic process, is crucial for the degradation or recycling of proteins and cellular components. Autophagy has a crucial role in several cellular functions and its dysregulation is associated with tumorigenesis, tumor-stroma interactions, and resistance to cancer therapy. A growing body of evidence shows that in multiple types of cancer, autophagy is also a key regulator in the tumor microenvironment and the cellular drug response. However, our understanding of the process of autophagy remains incompletely. In this review, we identify the role of autophagy and describe recent advances in the identification of the mechanism by which autophagy is implicated in drug resistance, with a focus on the mode of action, and validation as potential therapeutics.
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http://dx.doi.org/10.1016/j.biopha.2019.109415DOI Listing
November 2019

New insights into autophagy in hepatocellular carcinoma: mechanisms and therapeutic strategies.

Am J Cancer Res 2019 1;9(7):1329-1353. Epub 2019 Jul 1.

Department of General Surgery, The Fourth Affiliated Hospital, China Medical University Shenyang 110000, P. R. China.

Autophagy is a mechanism by which cellular substances are transported to lysosomes for degradation, allowing the basic transformation of cellular components, and providing energy and macromolecular precursors. In cancer, the contradictory role of autophagy in tumor suppression and promotion has been widely acknowledged. Activation and suppression of autophagy have been proposed as cancer therapies, resulting in targeted treatment of cancer by autophagy being considered ambiguous. The dynamic effect of autophagy can also be applied to hepatocellular carcinoma (HCC), a malignant tumor with high incidence and a low survival rate. In this review, we introduce characteristics of different types of autophagy and summarize which genes, non-coding RNAs, and related signaling pathways are involved in autophagy and the regulation of the formation and progress of HCC. More importantly, we discuss the role of autophagy in the treatment of HCC, such as in traditional chemotherapy, molecular targeted drugs, and natural products.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682711PMC
July 2019

Open reduction and plate fixation compared with non-surgical treatment for displaced midshaft clavicle fracture: A meta-analysis of randomized clinical trials.

Medicine (Baltimore) 2019 May;98(20):e15638

Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China.

Backgrounds: There is no consensus concerning whether surgery or non-surgical treatment is preferred for displaced midshaft clavicle fracture. We performed a meta-analysis of randomized controlled trials (RCTs) to compare healing effects and cosmetic results between surgery and non-surgery.

Methods: We retrieved RCTs regarding open reduction and plate fixation (ORPF) and non-surgical method for the treatment of displaced midshaft clavicle fracture published before June 2018 from PubMed, EMBASE and Cochrane Library. The difference between the two treatments was comparatively discussed in aspects of nonunion, malunion, functional outcome, cosmetic results, and complications.

Results: Nine RCTs were included. The results showed that ORPF is advantageous over the non-surgical treatment in terms of nonunion rate (RR, 0.11[95%CI, 0.06-0.23]), malunion rate (RR, 0.16[95%CI, 0.08-0.35]), appearance dissatisfaction rate (RR, 0.35[95%CI 0.23-0.55]), and shoulder appearance defect rate (RR, 0.06[95%CI, 0.02-0.17]). The non-surgical treatment showed lower rate of complication (RR, 1.60[95%CI, 1.02-2.53]) and no significant differences were found between the 2 treatment groups with respect to functional outcome (disabilities of the arm, shoulder and hand (DASH) questionnaire score) (MD, -4.17[95%CI, -9.35 to 1.01]).

Conclusions: This meta-analysis updated previous results. The current findings suggested that ORPF yielded better efficacy than conservation treatment for displaced midshaft clavicle fracture from perspectives of fracture healing and appearance.
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http://dx.doi.org/10.1097/MD.0000000000015638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531279PMC
May 2019

Pectoral nerve block in anesthesia for modified radical mastectomy: A meta-analysis based on randomized controlled trials.

Medicine (Baltimore) 2019 May;98(18):e15423

Department of Anesthesia, China-Japan Union Hospital of Jilin University.

Background: Many types of regional nerve blocks have been used during anesthesia for modified radical mastectomy. In recent years, the use of pectoral nerve (PECS) block has gained importance in postoperative analgesia, but there are still controversies regarding its efficacy. There is especially no consensus on the optimal type of PECS block to be used. Herein, we attempt to evaluate the analgesic efficacy of the PECS block after radical mastectomy.

Methods: We searched PubMed, EMBASE, and the Cochrane library for randomized controlled trials (RCTs) for studies regarding PECS versus general anesthesia (GA) that were published prior to May 31, 2018. Outcome measures such as intra- and postoperative consumption of opioids, postoperative nausea and vomiting (PONV), need for postoperative rescue analgesia, and pain scores were analyzed. After quality evaluation and data extraction, a meta-analysis was performed using Review Manager 5.3 software, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used for rating the quality of evidence.

Results: A total of 8 RCTs and 2 cohort studies involving 993 patients were eligible. Compared with the GA group, the PECS block group effectively reduced the intraoperative and postoperative use of opioid drugs, incidence of PONV, need for postoperative rescue analgesia, and pain scores within 0 to 6 hours after surgery. However, subgroup analysis showed that PECS I block did not have a significant advantage in reducing the intra- and postoperative consumption of opioids. Results for each outcome indicator were confirmed as having a high or moderate level of evidence.

Conclusions: Even considering the limitations (evaluations of efficacy in different age groups and for chronic pain were not carried out) of this meta-analysis, it can be concluded that the PECS II block is an effective anesthetic regimen in modified radical mastectomy that can effectively reduce the intra- and postoperative consumption of opioids, postoperative PONV, and the need for postoperative rescue analgesia and can alleviate early pain (0-6 hours) after surgery.
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http://dx.doi.org/10.1097/MD.0000000000015423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504333PMC
May 2019

Tumor organoids: From inception to future in cancer research.

Cancer Lett 2019 07 11;454:120-133. Epub 2019 Apr 11.

Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110000, PR China. Electronic address:

Tumor models have created new avenues for personalized medicine and drug development. A new culture model derived from a three-dimensional system, the tumor organoid, is gradually being used in many fields. An organoid can simulate the physiological structure and function of tissue in situ and maintain the characteristics of tumor cells in vivo, overcoming the disadvantages of traditional experimental tumor models. Organoids can mimic pathological features of tumors and maintain genetic stability, making them suitable for both molecular mechanism studies and pharmacological experiments of clinical transformation. In addition, the application of tumor organoids combined with other technologies, such as liquid biopsy technology, microraft array (MRA), and high-content screening (HCS), for the development of personalized diagnosis and cancer treatment has a promising future. In this review, we introduce the evolution of organoids and discuss their specific application and advantages. We also summarize the characteristics of several tumor organoids culture systems.
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http://dx.doi.org/10.1016/j.canlet.2019.04.005DOI Listing
July 2019

Long non-coding RNA HOTAIR promotes exosome secretion by regulating RAB35 and SNAP23 in hepatocellular carcinoma.

Mol Cancer 2019 04 3;18(1):78. Epub 2019 Apr 3.

Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.

Background: Emerging evidence indicates that tumor cells release a large amount of exosomes loaded with cargos during tumorigenesis. Exosome secretion is a multi-step process regulated by certain related molecules. Long non-coding RNAs (lncRNAs) play an important role in hepatocellular carcinoma (HCC) progression. However, the role of lncRNA HOTAIR in regulating exosome secretion in HCC cells remains unclear.

Methods: We analyzed the relationship between HOTAIR expression and exosome secretion-related genes using gene set enrichment analysis (GSEA). Nanoparticle tracking analysis was performed to validate the effect of HOTAIR on exosome secretion. The transport of multivesicular bodies (MVBs) after overexpression of HOTAIR was detected by transmission electron microscopy and confocal microscopy analysis of cluster determinant 63 (CD63) with synaptosome associated protein 23 (SNAP23). The mechanism of HOTAIR's regulation of Ras-related protein Rab-35 (RAB35), vesicle associated membrane protein 3 (VAMP3), and SNAP23 was assessed using confocal co-localization analysis, phosphorylation assays, and rescue experiments.

Results: We found an enrichment of exosome secretion-related genes in the HOTAIR high expression group. HOTAIR promoted the release of exosomes by inducing MVB transport to the plasma membrane. HOTAIR regulated RAB35 expression and localization, which controlled the docking process. Moreover, HOTAIR facilitated the final step of fusion by influencing VAMP3 and SNAP23 colocalization. In addition, we validated that HOTAIR induced the phosphorylation of SNAP23 via mammalian target of rapamycin (mTOR) signaling.

Conclusion: Our study demonstrated a novel function of lncRNA HOTAIR in promoting exosome secretion from HCC cells and provided a new understanding of lncRNAs in tumor cell biology.
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http://dx.doi.org/10.1186/s12943-019-0990-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446409PMC
April 2019

Surgical versus nonsurgical treatment for scaphoid waist fracture with slight or no displacement: A meta-analysis and systematic review.

Medicine (Baltimore) 2018 Nov;97(48):e13266

Hand & Foot Surgery and Reparative & Reconstruction Surgery Center, The Second, Hospital of Jilin University, Changchun, China.

Background: Surgical or nonsurgical treatment for scaphoid waist fracture with slight or no displacement is still controversial. This study compared the efficacy of the 2 methods through meta-analysis to provide a reference for the choice of clinical treatment options.

Methods: Two individuals independently searched for relevant RCTs and cohort studies from PubMed (1946-February 2018), Embase (1946-February 2018), and Cochrane library (1997-February 2018). After quality assessment and data extraction, Stata 14 software was used for combining the effect size, testing heterogeneity, and studying bias. GRADEpro was used to rate the level of evidence.

Results: Ten RCTs and 4 cohort studies with 765 patients were included. No statistical difference in satisfaction, pain, and Disability of the Arm, Shoulder, and Hand score was found after surgical and nonsurgical treatments. Compared with nonsurgical treatment, surgical treatment shortened the time to union (SMD = -5.01, 95% CI: -7.47 to -2.58, P = .000), decreased the convalescence (SMD = -2.09, 95% CI: -3.08 to -1.11, P = .000), and reduced the incidence of nonunion (RR = 0.47, 95% CI: 0.24-0.90), P = .023). Subgroup analyses showed that the percutaneous fixation treatment can shorten the time to union [SMD = -1.82, 95%CI (-2.22 to -1.42), P = = .000] and the convalescence (SMD = -4.26, 95%CI: -6.16 to -2.35, P = = .054), and open reduction fixation treatment can reduce the incidence of nonunion (RR = 0.20, 95%CI: 0.06-0.69, P = = .01).

Conclusion: For scaphoid waist fractures with slight or no displacement, there was no statistical difference in patient satisfaction, pain, and The Disability of the Arm, Shoulder, and Hand scores between surgical treatment and nonsurgical treatment. Closed surgical treatment can shorten the time to union and convalescence, and open reduction can reduce the incidence of nonunion. On the basis of this conclusion, chief physicians can consider which treatment to use according to the patient's clinical situation and their subjective intention.
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http://dx.doi.org/10.1097/MD.0000000000013266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283056PMC
November 2018

Yes-associated protein (YAP) binds to HIF-1α and sustains HIF-1α protein stability to promote hepatocellular carcinoma cell glycolysis under hypoxic stress.

J Exp Clin Cancer Res 2018 Sep 4;37(1):216. Epub 2018 Sep 4.

Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, 4 Chongshan East Street, Shenyang, Liaoning, 110032, People's Republic of China.

Background: Hypoxia-inducible factor 1α (HIF-1α) is essential in hepatocellular carcinoma (HCC) glycolysis and progression. Yes-associated protein (YAP) is a powerful regulator and is overexpressed in many cancers, including HCC. The regulatory mechanism of YAP and HIF-1α in HCC glycolysis is unknown.

Methods: We detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. The relationship between YAP mRNA expression and that of HIF-1α was analyzed using The Cancer Genome Atlas HCC tissue data. We cultured HepG2 and Huh7 HCC cells under normoxic (20% O) and hypoxic (1% O) conditions, and measured the lactate and glucose levels, migration and invasive capability, and the molecular mechanism of HCC cell glycolysis and progression.

Results: In this study, we detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. We observed that hypoxia-induced YAP activation is crucial for accelerating HCC cell glycolysis. Hypoxia inhibited the Hippo signaling pathway and promoted YAP nuclear localization, and decreased phosphorylated YAP expression in HCC cells. YAP knockdown inhibited HCC cell glycolysis under hypoxic. Mechanistically, hypoxic stress in the HCC cells promoted YAP binding to HIF-1α in the nucleus and sustained HIF-1α protein stability to bind to PKM2 gene and directly activates PKM2 transcription to accelerate glycolysis.

Conclusions: Our findings describe a new regulatory mechanism of hypoxia-mediated HCC metabolism, and YAP might be a promising therapeutic target in HCC.
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http://dx.doi.org/10.1186/s13046-018-0892-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123950PMC
September 2018

The role of YAP/TAZ activity in cancer metabolic reprogramming.

Mol Cancer 2018 09 3;17(1):134. Epub 2018 Sep 3.

Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, 4 Chongshan East Street, Shenyang, 110032, China.

In contrast to normal cells, which use the aerobic oxidation of glucose as their main energy production method, cancer cells prefer to use anaerobic glycolysis to maintain their growth and survival, even under normoxic conditions. Such tumor cell metabolic reprogramming is regulated by factors such as hypoxia and the tumor microenvironment. In addition, dysregulation of certain signaling pathways also contributes to cancer metabolic reprogramming. Among them, the Hippo signaling pathway is a highly conserved tumor suppressor pathway. The core oncosuppressive kinase cascade of Hippo pathway inhibits the nuclear transcriptional co-activators YAP and TAZ, which are the downstream effectors of Hippo pathway and oncogenic factors in many solid cancers. YAP/TAZ function as key nodes of multiple signaling pathways and play multiple regulatory roles in cancer cells. However, their roles in cancer metabolic reprograming are less clear. In the present review, we examine progress in research into the regulatory mechanisms of YAP/TAZ on glucose metabolism, fatty acid metabolism, mevalonate metabolism, and glutamine metabolism in cancer cells. Determining the roles of YAP/TAZ in tumor energy metabolism, particularly in relation to the tumor microenvironment, will provide new strategies and targets for the selective therapy of metabolism-related cancers.
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http://dx.doi.org/10.1186/s12943-018-0882-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122186PMC
September 2018

Long non-coding RNA CASC2 inhibits breast cancer cell growth and metastasis through the regulation of the miR-96-5p/SYVN1 pathway.

Int J Oncol 2018 Nov 13;53(5):2081-2090. Epub 2018 Aug 13.

Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.

Cancer susceptibility candidate 2 (CASC2), a long non-coding RNA (lncRNA), has been demonstrated to be a tumor suppressor in several types of cancer. However, the role and mechanism of CASC2 in breast cancer (BC) have not been investigated. In the present study, the expression and functions of CASC2 in BC were investigated. The expression of CASC2 was significantly decreased in BC tissues and cells compared with adjacent normal tissues and mammary epithelial cells, respectively. CASC2 overexpression inhibited the viability, migration and invasion, and elevated apoptosis of BC cells. In addition, CASC2 acted as a competing endogenous RNA for hsa-microRNA (miR)-96-5p and regulated the expression of its target gene, synoviolin (SYVN1). In miR-96-5p-overexpressed MDA-MB-231 cells, cell viability, migration and invasion was increased, and cell apoptosis was decreased, which was reversed by the upregulation of SYVN1. Taken together, the present study data indicated that decreased SYVN1 expression was a tumor suppressor, which inhibited the growth and metastasis of BC through the miR-96-5p/SYVN1 axis.
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http://dx.doi.org/10.3892/ijo.2018.4522DOI Listing
November 2018

Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/β-catenin signaling pathway activation in hepatocellular carcinoma cells.

J Exp Clin Cancer Res 2018 Jan 19;37(1). Epub 2018 Jan 19.

Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.

Background: Autophagy is a dynamic physiological process that can generate energy and nutrients for cell survival during stress. Autophagy can regulate the migration and invasive ability in cancer cells. However, the connection between autophagy and metabolism is unclear. Monocarboxylate transporter 1 (MCT1) plays an important role in lactic acid transport and H clearance in cancer cells, and Wnt/β-catenin signaling can increase cancer cell glycolysis. We investigated whether autophagy promotes glycolysis in hepatocellular carcinoma (HCC) cells by activating the Wnt/β-catenin signaling pathway, accompanied by MCT1 upregulation.

Methods: Autophagic activity was evaluated using western blotting, immunoblotting, and transmission electron microscopy. The underlying mechanisms of autophagy activation on HCC cell glycolysis were studied via western blotting, and Transwell, lactate, and glucose assays. MCT1 expression was detected using quantitative reverse transcription-PCR (real-time PCR), western blotting, and immunostaining of HCC tissues and the paired adjacent tissues.

Results: Autophagy promoted HCC cell glycolysis accompanied by MCT1 upregulation. Wnt/β-catenin signaling pathway activation mediated the effect of autophagy on HCC cell glycolysis. β-Catenin downregulation inhibited the autophagy-induced glycolysis in HCC cells, and reduced MCT1 expression in the HCC cells. MCT1 was highly expressed in HCC tissues, and high MCT1 expression correlated positively with the expression of microtubule-associated protein light chain 3 (LC3).

Conclusion: Activation of autophagy can promote metastasis and glycolysis in HCC cells, and autophagy induces MCT1 expression by activating Wnt/β-catenin signaling. Our study describes the connection between autophagy and glucose metabolism in HCC cells and may provide a potential therapeutic target for HCC treatment.
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http://dx.doi.org/10.1186/s13046-018-0673-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775607PMC
January 2018

The emerging role of exosome-derived non-coding RNAs in cancer biology.

Cancer Lett 2018 02 26;414:107-115. Epub 2017 Oct 26.

Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China. Electronic address:

Exosomes are a new means of intercellular information exchange that have aroused great research interest. Long neglected in research, exosomes were deemed nonfunctional cellular components to be discarded. However, it has been gradually revealed that exosomes are an important tool for the exchange of intercellular information and material. Exosomes contain specific repertoires of non-coding RNAs (ncRNAs, including microRNA and lncRNA), indicating that a specific RNA sorting mechanism may exist. Correspondingly, intracellular multivesicular bodies (MVBs) are produced after fusion with the cell membrane to release exosomes rather than inducing autophagy, which reveals that there may be a specific regulatory mechanism for MVB secretion. Cells can trigger cancer-related disorders after the recognition and uptake of circulating exosomal ncRNAs, providing indications for early tumor biopsy and treatment. The use of exosomes as a biological carrier in targeted therapy has been demonstrated. However, there may be a specific, unknown switch for loading drugs. This review focuses on the mechanisms of exosome biogenesis, release, and uptake. We also review the promotion of tumor development by exosomal ncRNAs including chemotherapy resistance, metastasis and the prospective use of exosomes in cancer diagnosis and treatment.
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http://dx.doi.org/10.1016/j.canlet.2017.10.040DOI Listing
February 2018

Promotion of glycolysis by HOTAIR through GLUT1 upregulation via mTOR signaling.

Oncol Rep 2017 Sep 20;38(3):1902-1908. Epub 2017 Jul 20.

Department of General Surgery, The Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning 110004, P.R. China.

The long non-coding RNA HOX transcript antisense RNA (HOTAIR) plays a key role in the progression of various carcinomas. However, whether or not HOTAIR influences glucose metabolism and the specific underlying mechanism in hepatocellular carcinoma (HCC) cells remain unclear. In the present study, we found markedly increased HOTAIR expression in 84 HCC tissues and demonstrated that HOTAIR overexpression promoted cell proliferation using Cell Counting Kit-8. The effect on glucose metabolism regulated by HOTAIR in HCC cells was determined by detecting lactate and glucose levels: HOTAIR promoted glycolysis by upregulating glucose transporter isoform 1 (GLUT1) and activating mammalian target of rapamycin (mTOR) signaling, whereas knockdown of HOTAIR suppressed this effect. Our research reveals a novel relationship between HOTAIR and glucose metabolism in HCC cells, and it may be a therapeutic target for diagnosing and treating HCC.
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http://dx.doi.org/10.3892/or.2017.5840DOI Listing
September 2017

Extracellular HSP70/HSP70-PCs regulate hepatocarcinoma cell migration and invasion via RhoA.

Oncol Lett 2017 Mar 30;13(3):1095-1100. Epub 2016 Dec 30.

Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China.

The effects of heat shock protein 70 (HSP70)/HSP70-peptide complexes (HSP70-PCs) on the invasion and metastasis ability of hepatocellular carcinoma (HCC) Huh-7 cells were investigated. Wound healing assay revealed that cells treated with HSP70/HSP70-PCs healed faster than negative control cells. HSP70/HSP70-PCs-treated cells also exhibited better migration ability and higher invasion ability than control cells. HSP70/HSP70-PCs treatment did not alter the messenger RNA (mRNA) or protein levels of matrix metalloproteinase-9; the opposite was true for Ras homolog family member A (RhoA) mRNA and protein levels. RNA interference of RhoA attenuated the migration of HSP70/HSP70-PCs-treated cells. The present findings indicate that regulation of HCC cell migration by HSP70/HSP70-PCs occurs via regulation of RhoA expression.
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http://dx.doi.org/10.3892/ol.2016.5551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403325PMC
March 2017

Transforming growth factor-beta1 suppresses hepatocellular carcinoma proliferation via activation of Hippo signaling.

Oncotarget 2017 May;8(18):29785-29794

Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, P. R. China.

In this study, we examined the expression of core proteins of the Hippo signaling pathway in hepatocellular carcinoma (HCC) cells treated with transforming growth factor-β 1(TGF-β1) and investigated the relationship between TGF-β1 and the Hippo signaling pathway, in order to better understand their roles in HCC and their potential implications for cancer therapy. We prove that the Hippo signaling pathway is involved in the TGF-β1-induced inhibition of the growth of HCC cells. Large tumor suppressor expression (LATS1) was overexpression and yes association protein 1(YAP1) translocated from the nucleus to the cytoplasm in HCC cells treated with TGF-β1. Overexpression of LATS1 and the nucleocytoplasmic translocation of YAP1 play an anti-oncogenetic role in the occurrence and development of liver cancer. Our findings provide new insight into strategies for liver cancer therapy.
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http://dx.doi.org/10.18632/oncotarget.14523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444703PMC
May 2017