Publications by authors named "Weihua Qiu"

73 Publications

The cross-talk between tumor cells and activated fibroblasts mediated by lactate/BDNF/TrkB signaling promotes acquired resistance to anlotinib in human gastric cancer.

Redox Biol 2021 Jul 20;46:102076. Epub 2021 Jul 20.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address:

Acquired resistance to tyrosine kinase inhibitors (TKIs) is the major obstacle to improve clinical efficacy in cancer patients. The epithelial-stromal interaction in tumor microenvironment influences cancer drug response to TKIs. Anlotinib is a novel oral multi-targeted TKI, and has recently been proven to be effective and safe for several tumors. However, if and how the epithelial-stromal interaction in tumor microenvironment affects anlotinib response in gastric cancer (GC) is not known. In this study, we found that anlotinib inhibited GC cells growth by inducing GC cells apoptosis and G2/M phase arrest in a dose- and time-dependent manner. Reactive oxygen species (ROS) mediated anlotinib-induced apoptosis in GC cells, while cancer-associated fibroblasts (CAFs) significantly suppressed anlotinib-induced apoptosis and ROS in GC cells. Increased BDNF that was derived from CAFs activated TrkB-Nrf2 signaling in GC cells, and reduced GC cells response to anlotinib. We identified secreted lactate from GC cells as the key molecule instructing CAFs to produce BDNF in a NF-κB-dependent manner. Additionally, functional targeting BDNF-TrkB pathway with neutralizing antibodies against BDNF and TrkB increased the sensitivity of GC cells towards anlotinib in human patient-derived organoid (PDO) model. Taken together, these results characterize a critical role of the epithelial-stroma interaction mediated by the lactate/BDNF/TrkB signaling in GC anlotinib resistance, and provide a novel option to overcome drug resistance.
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http://dx.doi.org/10.1016/j.redox.2021.102076DOI Listing
July 2021

A native cell membrane nanoparticles system allows for high-quality functional proteoliposome reconstitution.

BBA Adv 2021 5;1. Epub 2021 Apr 5.

Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, United States.

Proteoliposomes mimic the cell membrane environment allowing for structural and functional membrane protein analyses as well as antigen presenting and drug delivery devices. To make proteoliposomes, purified functional membrane proteins are required. Detergents have traditionally been used for the first step in this process However, they can irreversibly denature or render membrane proteins unstable, and the necessary removal of detergents after reconstitution can decrease proteoliposome yields. The recently developed native cell membrane nanoparticles (NCMN) system has provided a variety of detergent-free alternatives for membrane protein preparation for structural biology research. Here we attempt to employ the MCMN system for the functional reconstitution of channels into proteoliposomes. NCMN polymers NCMNP1-1 and NCMNP7-1, members of a NCMN polymer library that have been successful in extraction and affinity purification of a number of intrinsic membrane proteins, were selected for the purification and subsequent reconstitution of three bacterial channels: KcsA and the mechanosensitive channels of large and small conductance (MscL and MscS). We found that channels in NCMN particles, which appeared to be remarkably stable when stored at 4 °C, can be reconstituted into bilayers by simply incubating with lipids. We show that the resulting proteoliposomes can be patched for electrophysiological studies or used for the generation of liposome-based nanodevices. In sum, the findings demonstrate that the NCMN system is a simple and robust membrane protein extraction and reconstitution approach for making high-quality functional proteoliposomes that could significantly impact membrane protein research and the development of nanodevices.
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http://dx.doi.org/10.1016/j.bbadva.2021.100011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294337PMC
April 2021

Grass carp (Ctenopharyngodon idella) interferon regulatory factor 8 down-regulates interferon1 expression via interaction with interferon regulatory factor 2 in vitro.

Mol Immunol 2021 Jul 16;137:202-211. Epub 2021 Jul 16.

School of Life Science, Nanchang University, Nanchang, 330031, China. Electronic address:

Interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence-binding protein (ICSBP), is a negative regulatory factor of interferon (IFN) and plays an important role in cell differentiation and innate immunity in mammals. In recent years, some irf8 homologous genes have been cloned and confirmed to take part in innate immune response in fish, but the mechanism still remains unclear. In this paper, a grass carp (Ctenopharyngodon idella) irf8 gene (Ciirf8) was cloned and characterized. The deduced protein (CiIRF8) possesses a highly conserved N-terminal DNA binding domain but a less well-conserved C-terminal IRF association domain (IAD). Ciirf8 was widely expressed in all tested tissues of grass carp and up-regulated following poly(I:C) stimulation. Ciirf8 expression was also up-regulated in CIK cells upon treatment with poly(I:C). To explore the molecular mechanism of how fish IRF8 regulates ifn1 expression, the similarities and differences of grass carp IRF8 and IRF2 were compared and contrasted. Subcellular localization analysis showed that CiIRF8 is located both in the cytoplasm and nucleus; however, CiIRF2 is only located in the nucleus. The nuclear-cytoplasmic translocation of CiIRF8 was observed in CIK cells under stimulation with poly(I:C). The interaction of CiIRF8 and CiIRF2 was further confirmed by a co-immunoprecipitation assay in the nucleus. Dual-luciferase reporter assays showed that the promoter activity of Ciifn1 was significantly inhibited by co-transfection with CiIRF2 and CiIRF8. The transcription inhibition of Ciifn1 was alleviated by competitive binding of CiIRF2 and CiIRF8 to CiIRF1. In conclusion, CiIRF8 down-regulates Ciifn1 expression via interaction with CiIRF2 in cells.
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http://dx.doi.org/10.1016/j.molimm.2021.04.020DOI Listing
July 2021

Grass carp (Ctenopharyngodon idellus) SHP2 suppresses IFN I expression via decreasing the phosphorylation of GSK3β in a non-contact manner.

Fish Shellfish Immunol 2021 Jul 12;116:150-160. Epub 2021 Jul 12.

School of Life Science, Nanchang University, Nanchang, 330031, Jiangxi, China. Electronic address:

As a tyrosine phosphatase, Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) serves as an inhibitor in PI3K-Akt pathway. In mammals, SHP2 can phosphorylate GSK3β at Y216 site to control the expression of IFN. So far, the multiple functions of SHP2 have been reported in mammals. However, little is known about fish SHP2. In this study, we cloned and identified a grass carp (Ctenopharyngodon idellus) SHP2 gene (CiSHP2, MT373151). SHP2 is conserved among different vertebrates by amino acid sequences alignment and the phylogenetic tree analysis. CiSHP2 shared the closest homology with Danio rerio SHP2. Simultaneously, SHP2 was also tested in grass carp tissues and CIK (C. idellus kidney) cells. We found that it responded to poly I:C stimulation. CiSHP2 was located in the cytoplasm just as the same as those of mammals. Interestingly, it inhibited the phosphorylation level of GSK3β in a non-contact manner. Meanwhile CiGSK3β interacted with and directly phosphorylated CiTBK1. In addition, we found that CiSHP2 also reduced the phosphorylation level of CiTBK1 by CiGSK3β, and then it depressed the expression of IFN I via GSK3β-TBK1 axis. These results suggested that CiSHP2 was involved in CiGSK3β and CiTBK1 activity but not regulated their transcriptional level. At the same time, we also found that CiSHP2 also influenced the activity of CiIRF3. Therefore, fish SHP2 inhibited IFN I expression through blocking GSK3β-TBK1 signal axis.
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http://dx.doi.org/10.1016/j.fsi.2021.07.005DOI Listing
July 2021

The role of anlotinib-mediated EGFR blockade in a positive feedback loop of CXCL11-EGF-EGFR signalling in anaplastic thyroid cancer angiogenesis.

Br J Cancer 2021 Jun 4. Epub 2021 Jun 4.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: Hypoxia-induced angiogenesis functions importantly in anaplastic thyroid cancer (ATC) progression. However, the therapeutic potential of broad-spectrum anti-angiogenic agent remains undefined. Anlotinib conventionally targets VEGFR, FGFR and PDGFR. Here, a novel role of anlotinib on ATC angiogenesis was illustrated.

Methods: Molecular expressions were established via tissue microarray. Multiple assays (tubule formation, 3D sprouting and chicken chorioallantoic membrane model) were used for angiogenic evaluation. Panels of molecular screening were achieved by antibody and PCR arrays. The loop binding motif of EGFR for homology modelling was prepared using Maestro.

Results: Anlotinib could dose- and time-dependently inhibit cell viability under normoxia and hypoxia and could repress hypoxia-activated angiogenesis more efficiently in vitro and in vivo. CXCL11 and phospho-EGFR were hypoxia-upregulated with a positive correlation. The cancer-endothelium crosstalk could be mediated by the positive CXCL11-EGF-EGFR feedback loop, which could be blocked by anlotinib directly targeting EGFR via a dual mechanism by simultaneous inhibitory effects on cancer and endothelial cells. The AKT-mTOR pathway was involved in this regulatory network.

Conclusions: The newly identified CXCL11-EGF-EGFR signalling provided mechanistic insight into the interaction between cancer and endothelial cells under hypoxia, and EGFR was a novel target. Anlotinib may be the encouraging therapeutic candidate in ATC.
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http://dx.doi.org/10.1038/s41416-021-01340-xDOI Listing
June 2021

Predictive factors for prolonged operative time of robotic thyroidectomy via bilateral axillo-breast approach: Analysis of 359 cases of differentiated thyroid cancer.

Asian J Surg 2021 Apr 17. Epub 2021 Apr 17.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, PR China. Electronic address:

Objective: This study assessed the results of robotic thyroidectomy for differentiated thyroid cancer in early stage, to identify the predictive factors of operative time and complication rate.

Methods: A patient cohort of 359 cases in total was involved in this retrospective study. The data of clinical characteristics and follow-up results were collected.

Results: The cohort of patients involved was composed of 285 female patients and 74 male ones. The mean age was 34.91 ± 7.93 years old. The mean Body Mass Index (BMI) was 22.43 ± 3.47. The mean tumor size was 0.75 ± 0.56 cm, and the mean gland size was 4.68 ± 0.83 cm. Among all the specimen, the ratio of tumor invasion of gland capsule was 63/296, and the ratio of chronic thyroiditis was 110/249. 75 patients underwent total thyroidectomy + central compartment node dissection (CCND). 284 patients underwent Lobectomy + CCND. The ratio of central lymph node metastasis was 144/215 (40.1%). The mean number of lymph node dissected was 5.26 ± 4.09. The mean operative time was 96.53 ± 25.69 min. 21(5.8%) patients had hoarseness after operation. 22(29.3%) patients had hypocalcemia after total thyroidectomy. The inadvertent parathyroidectomy was found in 66(18.4%) cases. The surgical extent (unilateral/bilateral resection), BMI and gland size were found to have a significantly correlation with the operative time (p < 0.05) after multivariate analysis.

Conclusion: The surgical extent, BMI and gland size are found to be independent risk factors of prolonged operative time of robotic thyroidectomy. However, these factors are not associated with a higher complication rate.
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http://dx.doi.org/10.1016/j.asjsur.2021.03.030DOI Listing
April 2021

A property fine-tuned sulfobetaine cholesterol derivative for membrane protein structural biology.

Biochim Biophys Acta Gen Subj 2021 Jul 10;1865(7):129908. Epub 2021 Apr 10.

Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA; Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23219, USA. Electronic address:

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http://dx.doi.org/10.1016/j.bbagen.2021.129908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165746PMC
July 2021

Thyroidectomy for thyroid cancer via transareola single-site endoscopic approach: results of a case-match study with large-scale population.

Surg Endosc 2021 Mar 29. Epub 2021 Mar 29.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Background: Due to technical challenges, single-site endoscopic thyroidectomy (SSET) is seldom reported and has been attempted in only limited cases. This large-scale study aimed to compare the clinical outcomes of standardized transareola SSET (TASSET) with those of conventional open thyroidectomy (COT) for thyroid cancer.

Methods: The data were prospectively collected, and case-match study was performed at a ratio of 1:1 according to age, sex, body mass index, lesion size, number of lesion foci, lesion side, recurrent laryngeal nerve (RLN) exploration and pathology. Two hundred eligible patients underwent TASSET, and the same number of patients was selected for propensity score matching from 2256 patients who underwent COT. Perioperative data, including surgical profile, oncological and traumatic burdens, and cosmetic satisfaction, were analyzed.

Results: No significant differences were observed in blood loss or drainage between TASSET and COT groups. There were no differences in operation time between TASSET and COT (106.39 ± 28.44 vs 102.55 ± 23.10 min, p = 0.154). A total of 3.63 ± 1.82 lymph nodes (LNs) were retrieved from CND with 0.96 ± 1.42 positive in TASSET. In COT, the total and positive LN yields were 3.77 ± 1.91 and 0.99 ± 1.40 (p = 0.445, p = 0.802). Cancer recurrence was not observed in either group. There were no differences in the occurrence of permanent and transient hoarseness or RLN injuries. Postoperative flap seroma or hematoma occurred in 12 TASSET patients and 58 COT patients (p < 0.001). The pain score, CRP level and ESR in TASSET group were lower than those in COT group. TASSET yielded significantly better incision recovery and cosmetic scores than did COT at both the proliferation and stabilization stages.

Conclusions: TASSET is technically feasible and yields enhanced recovery with minimally invasive and cosmetic advantages without compromising the level of safety or cancer eradication.
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http://dx.doi.org/10.1007/s00464-021-08424-yDOI Listing
March 2021

Correction: Targeting tumor cell-derived CCL2 as a strategy to overcome Bevacizumab resistance in ETV5 colorectal cancer.

Cell Death Dis 2020 Nov 23;11(11):1006. Epub 2020 Nov 23.

Department of General Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025, Shanghai, China.

A Correction to this paper has been published: https://doi.org/10.1038/s41419-020-03208-z.
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http://dx.doi.org/10.1038/s41419-020-03208-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683607PMC
November 2020

Targeting tumor cell-derived CCL2 as a strategy to overcome Bevacizumab resistance in ETV5 colorectal cancer.

Cell Death Dis 2020 10 24;11(10):916. Epub 2020 Oct 24.

Department of General Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025, Shanghai, China.

In our previous study, ETV5 mediated-angiogenesis was demonstrated to be dependent upon the PDGF-BB/PDGFR-β/Src/STAT3/VEGFA pathway in colorectal cancer (CRC). However, the ability of ETV5 to affect the efficacy of anti-angiogenic therapy in CRC requires further investigation. Gene set enrichment analysis (GSEA) and a series of experiments were performed to identify the critical candidate gene involved in Bevacizumab resistance. Furthermore, the ability of treatment targeting the candidate gene to enhance Bevacizumab sensitivity in vitro and in vivo was investigated. Our results revealed that ETV5 directly bound to the VEGFA promoter to promote translation of VEGFA. However, according to in vitro and in vivo experiments, ETV5 unexpectedly accelerated antiVEGF therapy (Bevacizumab) resistance. GSEA and additional assays confirmed that ETV5 could promote angiogenesis by inducing the secretion of another tumor angiogenesis factor (CCL2) in CRC cells to facilitate Bevacizumab resistance. Mechanistically, ETV5 upregulated CCL2 by activating STAT3 to facilitate binding with the CCL2 promoter. ETV5 induced-VEGFA translation and CCL2 secretion were mutually independent mechanisms, that induced angiogenesis by activating the PI3K/AKT and p38/MAPK signaling pathways in human umbilical vein endothelial cells (HUVECs). In CRC tissues, ETV5 protein levels were positively associated with CD31, CCL2, and VEGFA protein expression. CRC patients possessing high expression of ETV5/VEGFA or ETV5/CCL2 exhibited a poorer prognosis compared to that of other patients. Combined antiCCL2 and antiVEGFA (Bevacizumab) treatment could inhibit tumor angiogenesis and growth more effectively than single treatments in CRCs with high expression of ETV5 (ETV5 CRCs). In conclusion, our results not only revealed ETV5 as a novel biomarker for anti-angiogenic therapy, but also indicated a potential combined therapy strategy that involved in targeting of both CCL2 and VEGFA in ETV5 CRC.
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http://dx.doi.org/10.1038/s41419-020-03111-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585575PMC
October 2020

FGFR3 promotes tumor progression via the phosphorylation and destabilization of ten-eleven translocation-2 in human hepatocellular carcinoma.

Cell Death Dis 2020 10 23;11(10):903. Epub 2020 Oct 23.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Overexpression of fibroblast growth factor receptor 3 (FGFR3) correlates with more severe clinical features of hepatocellular carcinoma (HCC). Our previous study has shown that FGFR3, a novel splicing mutation of FGFR3, contributes significantly to HCC malignant character, but the epigenetic mechanism is still elusive. In this study, through mass spectrometry and co-immunoprecipitation studies, we discover a close association between FGFR3 and the DNA demethylase Ten-Eleven Translocation-2 (TET2). Unlike other certain types of cancer, mutation of TET2 is rare in HCC. However, activation of FGFR3 by FGF1 dramatically shortens TET2 half-life. FGFR3, but not wild-type FGFR3, directly interacts with TET2 and phosphorylates TET2 at Y1902 site, leading to the ubiquitination and proteasome-mediated degradation of TET2. Overexpression of a phospho-deficient mutant TET2 (Y1902F) significantly reduces the oncogenic potential of FGFR3 in vitro and in vivo. Furthermore, FGFR3 significantly enhances HCC cell proliferation through the TET2-PTEN-AKT pathway. Specifically, TET2 offsets the elevation of p-AKT level induced by FGFR3 through directly binding to PTEN promoter and increasing 5-hmC. Therefore, through phosphorylation and inhibition of TET2, FGFR3 reduces PTEN expression and substantiates AKT activation to stimulate HCC proliferation. Together, this study identifies TET2 as a key regulator of the oncogenic role of FGFR3 in HCC carcinogenesis and sheds light on new therapeutic strategies for HCC treatment.
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http://dx.doi.org/10.1038/s41419-020-03089-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584635PMC
October 2020

Identification and validation of critical alternative splicing events and splicing factors in gastric cancer progression.

J Cell Mol Med 2020 11 16;24(21):12667-12680. Epub 2020 Sep 16.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Gene expression and alternative splicing (AS) interact in complex ways to regulate biological process which is associated with cancer development. Here, by integrated analysis of gene expression and AS events, we aimed to identify the hub AS events and splicing factors relevant in gastric cancer development (GC). RNA-seq data, clinical data and AS events of 348 GC samples were obtained from the TCGA and TCGASpliceSeq databases. Cox univariable and multivariable analyses, KEGG and GO pathway analyses were performed to identify hub AS events and splicing factor/spliceosome genes, which were further validated in 53 GCs. By bioinformatics methods, we found that gene AS event- and gene expression-mediated GC progression shared the same mechanisms, such as PI3K/AKT pathway, but the involved genes were different. Though expression of 17 hub AS events were confirmed in 53 GC tissues, only 10 AS events in seven genes were identified as critical candidates related to GC progression, notably the AS events (Exon Skip) in CLSTN1 and SEC16A. Expression of these AS events in GC correlated with activation of the PI3K/AKT pathway. Genes with AS events associated with clinical parameters and prognosis were different from the genes whose mRNA levels were related to clinical parameters and prognosis. Besides, we further revealed that QKI and NOVA1 were the crucial splicing factors regulating expression of AS events in GC, but not spliceosome genes. Our integrated analysis revealed hub AS events in GC development, which might be the potential therapeutic targets for GC.
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http://dx.doi.org/10.1111/jcmm.15835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686978PMC
November 2020

Native Cell Membrane Nanoparticles System for Membrane Protein-Protein Interaction Analysis.

J Vis Exp 2020 07 16(161). Epub 2020 Jul 16.

Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University; Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University;

Protein-protein interactions in cell membrane systems play crucial roles in a wide range of biological processes- from cell-to-cell interactions to signal transduction; from sensing environmental signals to biological response; from metabolic regulation to developmental control. Accurate structural information of protein-protein interactions is crucial for understanding the molecular mechanisms of membrane protein complexes and for the design of highly specific molecules to modulate these proteins. Many in vivo and in vitro approaches have been developed for the detection and analysis of protein-protein interactions. Among them the structural biology approach is unique in that it can provide direct structural information of protein-protein interactions at the atomic level. However, current membrane protein structural biology is still largely limited to detergent-based methods. The major drawback of detergent-based methods is that they often dissociate or denature membrane protein complexes once their native lipid bilayer environment is removed by detergent molecules. We have been developing a native cell membrane nanoparticle system for membrane protein structural biology. Here, we demonstrate the use of this system in the analysis of protein-protein interactions on the cell membrane with a case study of the oligomeric state of AcrB.
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http://dx.doi.org/10.3791/61298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185428PMC
July 2020

Crystal structure of the catalytic subunit of bovine pyruvate dehydrogenase phosphatase.

Acta Crystallogr F Struct Biol Commun 2020 Jul 1;76(Pt 7):292-301. Epub 2020 Jul 1.

Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.

Mammalian pyruvate dehydrogenase (PDH) activity is tightly regulated by phosphorylation and dephosphorylation, which is catalyzed by PDH kinase isomers and PDH phosphatase isomers, respectively. PDH phosphatase isomer 1 (PDP1) is a heterodimer consisting of a catalytic subunit (PDP1c) and a regulatory subunit (PDP1r). Here, the crystal structure of bovine PDP1c determined at 2.1 Å resolution is reported. The crystals belonged to space group P321, with unit-cell parameters a = b = 75.3, c = 173.2 Å. The structure was solved by molecular-replacement methods and refined to a final R factor of 21.9% (R = 24.7%). The final model consists of 402 of a possible 467 amino-acid residues of the PDP1c monomer, two Mn ions in the active site, an additional Mn ion coordinated by His410 and His414, two MnSO ion pairs at special positions near the crystallographic twofold symmetry axis and 226 water molecules. Several new features of the PDP1c structure are revealed. The requirements are described and plausible bases are deduced for the interaction of PDP1c with PDP1r and other components of the pyruvate dehydrogenase complex.
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http://dx.doi.org/10.1107/S2053230X20007943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336360PMC
July 2020

Accelerates Hepatocellular Carcinoma Progression by Driving the Epithelial-to-Mesenchymal Transition.

Onco Targets Ther 2020 8;13:3931-3942. Epub 2020 May 8.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.

Introduction: A poor prognosis owing to cancer invasion and metastasis, hepatocellular carcinoma (HCC) is one of the leading causes of malignancy deaths worldwide. A dominant epithelial-to-mesenchymal transition or EMT function in tumour metastasis is substantially evidenced. Prior reports identified a likely correlation of the nuclear hormone receptor with HCC progression, but the underlying molecular mechanisms and role of invasion and metastasis are still to be adequately documented.

Methods: We carried out PROGgeneV2 platform database analysis and compared expression in HCC tissues with that in adjacent noncancerous tissues by Western blotting. Cell proliferation, invasion, and migration were also assessed using a lentivirus system. Moreover, the relevant signalling proteins were evaluated.

Results: The PROGgeneV2 platform database analysis suggested an upregulated expression related to poor overall survival, or OS, in HCC, with higher levels in HCC, compared to the adjoining non-cancerous tissue. Depleting decreased HCC cell proliferation, migration and invasion in vitro, whilst in vivo downregulation revealed fewer metastatic nodules in the lungs. Furthermore, knockdown amplified epithelial marker, namely E-cadherin expressions, and decreased mesenchymal markers, ie, N-cadherin and vimentin expressions, with β-catenin overexpression.

Conclusion: is shown to accelerate HCC progression via driving EMT.
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http://dx.doi.org/10.2147/OTT.S237804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217318PMC
May 2020

Short-term Outcomes After Robot-Assisted vs Open Pancreaticoduodenectomy After the Learning Curve.

JAMA Surg 2020 05;155(5):389-394

Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Importance: Robot-assisted pancreaticoduodenectomy (RPD) has been reported to be safe and feasible. As a new technique, RPD has a learning curve similar to that of other types of minimally invasive pancreatic surgery such as laparoscopic pancreaticoduodenectomy. To our knowledge, no reports exist on the outcomes of open pancreaticoduodenectomy (OPD) and RPD after the learning curve.

Objective: To analyze and evaluate the actual advantages of RPD.

Design, Setting, And Participants: Between May 2010 and December 2018, 450 patients underwent RPD in the Shanghai Ruijin Hospital affiliated with Shanghai Jiaotong University in Shanghai, China, a high-volume pancreatic disease center. According to our previous study, an important flexion point in the learning curve is 250 cases. Data on the last 200 RPD cases were collected from January 2017 to December 2018. During that period, 634 patients underwent OPD. These patients were divided into 2 groups, and propensity score matching was used to minimize bias. The demographic data and operative outcomes were collected and analyzed. Analysis began May 2019.

Exposures: Robot-assisted pancreaticoduodenectomy and OPD.

Main Outcomes And Measures: The short-term operative outcomes of RPD and OPD.

Results: After 1:1 matching, 187 cases of RPD and OPD were recorded. In the RPD group, 78 patients (41.7%) were women, and the mean (SD) age was 60.9 (11.4) years. In the OPD group, 80 patients (42.8%) were women, and the mean (SD) age was 60.1 (10.8) years. Robot-assisted pancreaticoduodenectomy had advantages in operative time (mean [SD], 279.7 [76.3] minutes vs 298.2 [78.3] minutes; P = .02), estimated blood loss (mean [SD], 297.3 [246.8] mL vs 415.2 [497.9] mL; P = .002), and postoperative length of hospital stay (mean [SD], 22.4 [16.7] days vs 26.1 [16.3] days; P = .03). However, there was no significant difference in the R0 resection rate and incidence rate of postoperative complications, such as postoperative pancreatic fistula, bile leak, and delayed gastric emptying. The incidence rates of postoperative bleeding and reoperation in the RPD group were similar to those in the OPD group, with no statistically significant difference.

Conclusions And Relevance: After passing the learning curve, RPD had advantages in operative time and blood loss compared with OPD. There were no differences in postoperative complications such as postoperative pancreatic fistula, bile leak, and delayed gastric emptying. However, patients recovered more quickly after RPD than after OPD. A prospective randomized clinical trial is needed in the future to verify these results.
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http://dx.doi.org/10.1001/jamasurg.2020.0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057168PMC
May 2020

Organ-specific regulation of CHD1 by acute PTEN and p53 loss in mice.

Biochem Biophys Res Commun 2020 05 27;525(3):614-619. Epub 2020 Feb 27.

Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, 46556, USA; Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN, 46556, USA; Tumor Microenvironment and Metastasis Program, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, 46202, USA. Electronic address:

Homozygous deletion of chromodomain helicase DNA binding protein 1 (CHD1) is among the most frequent genetic alterations in prostate cancer. CHD1 is converted from a non-essential to an essential gene for prostate cancer cell survival when phosphatase and tensin homolog (PTEN), another frequently deleted gene in prostate cancer, is disrupted. It remains unknown whether this PTEN-CHD1 genetic and functional relationship also operates in other solid tumors. Here, we address this question by using genetically engineered mouse models. Inducible deletion of Pten and p53 in all somatic cells of adult mice led to widespread PI3K/Akt pathway activation and hyperplastic phenotypes, causing multi-organ failure and lethality. Remarkably, when Chd1 was co-deleted in the Pten/p53 model, the lethality remained unperturbed. At the protein level, Chd1 was stabilized upon Pten deletion in prostate, but not in other organs examined (lung, liver, kidney, colon, mammary). These results shed mechanistic insight on the cancer type-specific copy number alteration pattern of PTEN and CHD1.
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http://dx.doi.org/10.1016/j.bbrc.2020.02.136DOI Listing
May 2020

MACC1-AS1 promotes hepatocellular carcinoma cell invasion and proliferation by regulating PAX8.

Aging (Albany NY) 2020 01 8;12(1):70-79. Epub 2020 Jan 8.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

Long noncoding RNAs play vital roles in several biological processes, including cell growth and embryonic development. We showed that MACC1-AS1 was overexpressed in hepatocellular carcinoma (HCC) cells and tissues. The MACC1-AS1 expression level was dramatically upregulated in HCC samples compared to adjacent normal samples, and 77.5% (31 of 40) of HCC samples showed overexpression of MACC1-AS1. Ectopic MACC1-AS1 expression enhanced cell proliferation and cyclin D1 expression in both SMMC7721 and MHCC-97H cells. Ectopic expression of MACC1-AS1 promoted vimentin, N-cadherin and snail expression and decreased E-cadherin expression in both SMMC7721 and MHCC-97H cells. MACC1-AS1 overexpression also induced cell invasion in the same two cell lines. Furthermore, MACC1-AS1 overexpression enhanced PAX8 expression in HCC cells. The PAX8 level was dramatically increased in HCC samples compared to adjacent normal samples, and 75% (30 of 40) of HCC samples showed overexpression of PAX8. PAX8 expression was positively correlated with MACC1-AS1 expression in HCC samples. MACC1-AS1 overexpression promoted HCC cell proliferation, EMT and invasion through regulating PAX8. These results suggest that MACC1-AS1 acts as an oncogene in the development of HCC.
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http://dx.doi.org/10.18632/aging.102585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977655PMC
January 2020

Claudin-1 silencing increases sensitivity of liver cancer HepG2 cells to 5-fluorouracil by inhibiting autophagy.

Oncol Lett 2019 Dec 8;18(6):5709-5716. Epub 2019 Oct 8.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.

Liver cancer is one of the most common cancer types globally. However, the acquisition of drug resistance limits the effectiveness of chemotherapy and commonly results in metastasis. Therefore, an effective therapeutic approach to target chemoresistance-associated cellular molecules is imperative. Claudin-1 (CLDN1) has previously been reported to be associated with the development of drug resistance. The present study investigated the effect of CLDN1 on the sensitivity of 5-fluorouracil (5-FU)-resistant liver cancer cells. Firstly, a 5-FU-resistant HepG2 liver cancer cell line (Hep/5FU) was developed by continuous 5-FU treatment. MTT proliferation, Transwell and Matrigel assays indicated that Hep/5FU cells were significantly resistant to 5-FU, and demonstrated increased migration and invasion abilities, compared with parental HepG2 cells. Furthermore, reverse transcription-quantitative polymerase chain reaction and western blot analysis indicated that mRNA and protein expression levels of CLDN1 were significantly increased in Hep/5FU cells, compared with HepG2 cells. CLDN1 was knocked down by transfection with small interference RNA. MTT and Annexin V-fluorescein isothiocyanate/propidium iodide assays demonstrated that CLDN1 silencing significantly inhibits proliferation and enhances apoptosis induced by 5-FU treatment in Hep/5FU cells, compared with non-silenced Hep/5FU cells. Additionally, CLDN1 silencing attenuated the migration and invasion capabilities of Hep/5FU cells. In addition, it was identified that CLDN1 silencing decreased drug resistance by inhibiting autophagy, which was associated with a decrease in the ratio of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II/LC3-I and upregulation of P62. A cell proliferation assay revealed that the addition of autophagy inhibitor 3-methyladenine decreased drug resistance of Hep/5FU cells. By contrast, incubation with the autophagy agonist Rapamycin elevated drug resistance of CLDN1-silenced Hep/5FU cells. In summary, these data indicate that CLDN1 may be a potential target for resensitizing resistant liver cancer HepG2 cells to 5-FU by regulating cell autophagy.
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http://dx.doi.org/10.3892/ol.2019.10967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865833PMC
December 2019

Learning Curve From 450 Cases of Robot-Assisted Pancreaticoduocectomy in a High-Volume Pancreatic Center: Optimization of Operative Procedure and a Retrospective Study.

Ann Surg 2019 Oct 22. Epub 2019 Oct 22.

Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Objective: We aimed to describe our experience and the learning curve of 450 cases of robot-assisted pancreaticoduodenectomy (RPD) and optimize the surgical process so that our findings can be useful for surgeons starting to perform RPD.

Summary Background Data: Robotic surgical systems were first introduced 20 years ago. Pancreaticoduodenectomy (PD) is a challenging surgery because of its technical difficulty. RPD may overcome some of these difficulties.

Methods: The medical records of 450 patients who underwent RPD between May 2010 and December 2018 at the Shanghai Ruijin Hospital were retrospectively analyzed. Operative times and estimated blood loss (EBL) were analyzed and the learning curve was determined. A cumulative sum (CUSUM) analysis was used to identify the inflexion points. Other postoperative outcomes, postoperative complications, and long-term follow-up were also analyzed.

Results: Operative time improved gradually over time from 405.4 ± 112.9 minutes (case 1-50) to 273.6 ± 70 minutes (case 301-350) (P < 0.001). EBL improved from 410 ± 563.5 mL (case 1-50) to 149.0 ± 103.3 mL (case 351-400) (P < 0.001). According to the CUSUM curve, there were 3 phases in the RPD learning curve. The inflexion points were around cases 100 and 250. The incidence of pancreatic leak in the last 350 cases was significantly lower than that in the first 100 cases (30.0% vs 15.1%, P = 0.003).

Conclusions: RPD is safe and feasible for selected patients. Operative and oncologic outcomes were much improved after experience of 250 cases. Our optimization of the surgical process may have also contributed to this. Future prospective and randomized studies are needed to confirm our results.
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http://dx.doi.org/10.1097/SLA.0000000000003664DOI Listing
October 2019

Cell-Cycle-Dependent Phosphorylation of PRPS1 Fuels Nucleotide Synthesis and Promotes Tumorigenesis.

Cancer Res 2019 Sep 28;79(18):4650-4664. Epub 2019 Jun 28.

Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Nucleotide supply is essential for DNA replication in proliferating cells, including cancer cells. Ribose-phosphate diphosphokinase 1 (PRPS1) is a key enzyme to produce the consensus precursor of nucleotide synthesis. PRPS1 participates in the pentose phosphate pathway (PPP) by catalyzing the phosphoribosylation of D-ribose 5-phosphate (R-5P) to 5-phosphoribosyl-1-pyrophosphate. Therefore, PRPS1 not only controls purine biosynthesis and supplies precursors for DNA and RNA biosynthesis but also regulates PPP through a feedback loop of the PRPS1 substrate R-5P. However, it is still elusive whether PRPS1 enhances nucleotide synthesis during cell-cycle progression. In this study, we explore the role and activation mechanism of PRPS1 in cell-cycle progression of colorectal cancer, and observed a peak in its enzymatic activity during S phase. CDK1 contributes to upregulation of PRPS1 activity by phosphorylating PRPS1 at S103; loss of phosphorylation at S103 delayed the cell cycle and decreased cell proliferation. PRPS1 activity in colorectal cancer samples is higher than in adjacent tissue, and the use of an antibody that specifically detects PRPS1 phosphorylation at S103 showed consistent results in 184 colorectal cancer tissues. In conclusion, compared with upregulation of PRPS1 expression levels, increased PRPS1 activity, which is marked by S103 phosphorylation, is more important in promoting tumorigenesis and is a promising diagnostic indicator for colorectal cancer. SIGNIFICANCE: These findings show that the enzymatic activity of PRPS1 is crucial for cell-cycle regulation and suggest PRPS1 phosphorylation at S103 as a direct therapeutic target and diagnostic biomarker for colorectal cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2486DOI Listing
September 2019

Corrigendum to "Targeting autophagy enhances apatinib-induced apoptosis via endoplasmic reticulum stress for human colorectal cancer" [Cancer Lett. 431 (2018) 105-114].

Cancer Lett 2019 Oct 4;461:156. Epub 2019 Jun 4.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Department of General Surgery, Ruijin North Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201800, China. Electronic address:

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http://dx.doi.org/10.1016/j.canlet.2019.05.020DOI Listing
October 2019

INTS8 accelerates the epithelial-to-mesenchymal transition in hepatocellular carcinoma by upregulating the TGF-β signaling pathway.

Cancer Manag Res 2019 26;11:1869-1879. Epub 2019 Feb 26.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China,

Background: Hepatocellular carcinoma (HCC) is the third leading cause of death by malignancy worldwide. HCC has a poor prognosis due to tumor invasiveness and metastasis. There is substantial evidence that the epithelial-to-mesenchymal transition (EMT) plays a central role in cancer metastasis. In a previous study, a possible association between integrator complex 8 (INTS8) and the progression and development of HCC was discovered. However, its role and the molecular mechanisms in HCC are poorly understood.

Methods: The PROGgeneV2 platform database and Kaplan-Meier plotter analysis were used to analyze the potential effects of INTS8 in HCC. Moreover, we performed migration, transwell, and metastasis assays to investigate the effects of INTS8 on HCC cells. In addition, relevant signaling pathways were examined by western blot and RT-qPCR assays.

Results: We used the PROGgeneV2 platform database and Kaplan-Meier plotter analysis, which indicated that increased expression of INTS8 is associated with poor overall survival of HCC. Moreover, INTS8 expression was higher in HCC tissues than in adjacent noncancerous tissues. INTS8 depletion reduced the invasion and migration of HCC cell lines. Downregulation of INTS8 in vivo resulted in fewer observed metastatic nodules in lungs. Moreover, INTS8 knockdown also increased the expression of epithelial markers (E-cadherin) and decreased the expression of mesenchymal markers (N-cadherin and vimentin) following the downregulation of SMAD4. In addition, pretreatment with TGF-β1 could partly prevent the decrease in the expression of SMAD4 and EMT markers induced by INTS8 knockdown.

Conclusion: Overall, these findings suggest that INTS8 accelerates the EMT in HCC by upregulating the TGF-β signaling pathway.
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http://dx.doi.org/10.2147/CMAR.S184392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396674PMC
February 2019

ETS variant 5 promotes colorectal cancer angiogenesis by targeting platelet-derived growth factor BB.

Int J Cancer 2019 07 28;145(1):179-191. Epub 2019 Jan 28.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

ETS transcription factors play important roles in tumor cell invasion, differentiation and angiogenesis. In this study, we initially demonstrated that ETS translocation variant 5 (ETV5) is abnormally upregulated in colorectal cancer (CRC), is positively correlated with CRC tumor size, lymphatic metastasis and tumor node metastasis (TNM) stage and indicates shorter survival and disease-free survival in CRC patients. In vitro and in vivo experiments revealed that the downregulation of ETV5 could significantly suppress CRC cell proliferation. Moreover, overexpression of ETV5 could stimulate CRC angiogenesis in vitro and in vivo, which is consistent with RNA-seq results. Then, we identified platelet-derived growth factor BB (PDGF-BB) as a direct target of ETV5 that plays an important role in ETV5-mediated CRC angiogenesis through an angiogenesis antibody microarray. Additionally, PDGF-BB could activate VEGFA expression via the PDGFR-β/Src/STAT3 pathway in CRC cells and appeared to be positively correlated with ETV5 in CRC tissues. Finally, we revealed that ETV5 could bind directly to the promoter region of PDGF-BB and regulate its expression through ChIP and luciferase assays. Overall, our study suggested that the transcription factor ETV5 could stimulate CRC malignancy and promote CRC angiogenesis by directly targeting PDGF-BB. These findings suggest that EVT5 may be a potential new diagnostic and prognostic marker in CRC and that targeting ETV5 might be a potential therapeutic option for inhibiting CRC angiogenesis.
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http://dx.doi.org/10.1002/ijc.32071DOI Listing
July 2019

Structure and activity of lipid bilayer within a membrane-protein transporter.

Proc Natl Acad Sci U S A 2018 12 3;115(51):12985-12990. Epub 2018 Dec 3.

Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298;

Membrane proteins function in native cell membranes, but extraction into isolated particles is needed for many biochemical and structural analyses. Commonly used detergent-extraction methods destroy naturally associated lipid bilayers. Here, we devised a detergent-free method for preparing cell-membrane nanoparticles to study the multidrug exporter AcrB, by cryo-EM at 3.2-Å resolution. We discovered a remarkably well-organized lipid-bilayer structure associated with transmembrane domains of the AcrB trimer. This bilayer patch comprises 24 lipid molecules; inner leaflet chains are packed in a hexagonal array, whereas the outer leaflet has highly irregular but ordered packing. Protein side chains interact with both leaflets and participate in the hexagonal pattern. We suggest that the lipid bilayer supports and harmonizes peristaltic motions through AcrB trimers. In AcrB D407A, a putative proton-relay mutant, lipid bilayer buttresses protein interactions lost in crystal structures after detergent-solubilization. Our detergent-free system preserves lipid-protein interactions for visualization and should be broadly applicable.
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http://dx.doi.org/10.1073/pnas.1812526115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304963PMC
December 2018

Intraoperative carbon nanoparticles mapping in secondary total thyroidectomy for recurrent thyroid nodules: Results of a 8-criterion case-match study (case control study).

Int J Surg 2018 Dec 23;60:210-215. Epub 2018 Nov 23.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address:

Background: The extent of total thyroidectomy in the management of multinodular goiter remains unclear. Compared to primary thyroidectomy, secondary total thyroidectomy is more difficult to perform and carries a significantly higher risk of postoperative complications such as recurrent laryngeal nerve (RLN) palsy or hypoparathyroidism. In this study, we aimed to evaluate the efficacy and safety of intraoperative carbon nanoparticle (CN) mapping in patients undergoing secondary total thyroidectomy.

Methods: We performed a case-matched analysis of a prospectively maintained database using 8 specific criteria to compare perioperative outcomes after primary total thyroidectomy to those after secondary total thyroidectomy with intraoperative CN mapping. The criteria included age, sex, operative procedure, RLN/parathyroid glands (PGs) exploration, preoperative vocal cord calcium abnormalities, and pathological results. Thirty-five patients underwent secondary total thyroidectomy with intraoperative CN mapping due to recurrent thyroid nodules or development of nodules suspicious for malignancy after subtotal thyroidectomy. Fifty exact matches for all 8 criteria were identified from the database in our previous study, which included records of 3078 primary thyroidectomies without CNs. Perioperative outcomes, surgical technique, and complications were analyzed.

Results: The RLNs were successfully identified in all 35 patients. Among three patients that experienced slight hoarseness, one had an RLN end-to-end anastomosis with subsequent improvement in the during the 12-month follow-up period. Two patients experienced changes in vocal tone, but recovered after several months. Two patients underwent parathyroid auto-transplantations, and subsequently presented with transient hypocalcaemia. Their symptoms gradually remitted within one year. Except for mean operation time, there were no statistically significant differences in complications between the primary total thyroidectomies and the secondary total thyroidectomy with CNs.

Conclusions: Intraoperative CN mapping, expert knowledge of the jugular anatomy, and standardized resection procedures can minimize the incidence of complications such as RLN palsy and hypoparathyroidism after secondary total thyroidectomy.
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http://dx.doi.org/10.1016/j.ijsu.2018.11.014DOI Listing
December 2018

Apatinib-induced protective autophagy and apoptosis through the AKT-mTOR pathway in anaplastic thyroid cancer.

Cell Death Dis 2018 10 9;9(10):1030. Epub 2018 Oct 9.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.

Apatinib, an inhibitor of vascular endothelial growth factor receptor-2, has been shown to promote anti-cancer action across a wide range of malignancies, including gastric, lung, and breast cancers. Our previous study showed that apatinib increases apoptosis in anaplastic thyroid carcinoma (ATC), but the direct functional mechanism of tumor lethality mediated by apatinib is still unknown. In this study, we demonstrated that apatinib induced both autophagy and apoptosis in human ATC cells through downregulation of p-AKT and p-mTOR signals via the AKT/mTOR pathway. Moreover, inhibition of apatinib-induced autophagy increased apatinib-induced apoptosis in ATC cells, and additional tumor suppression was critically produced by the combination of apatinib and the autophagy inhibitor chloroquine in vivo and in vitro. These findings showed that both autophagy and AKT/mTOR signals were engaged in ATC cell death evoked by apatinib. ATC patients might benefit from the new anti-cancer drug, and molecular targeted treatment in combination with autophagy inhibitors shows promise as a treatment improvement.
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http://dx.doi.org/10.1038/s41419-018-1054-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177436PMC
October 2018

Targeting autophagy enhances apatinib-induced apoptosis via endoplasmic reticulum stress for human colorectal cancer.

Cancer Lett 2018 09 30;431:105-114. Epub 2018 May 30.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Department of General Surgery, Ruijin North Hospital, Shanghai Jiaotong University School of Medicine, 201801, Shanghai, China. Electronic address:

Apatinib, a novel tyrosine kinase inhibitor (TKI), has been confirmed for its efficacy and safety in the treatment of advanced gastric carcinoma and some other solid tumors. However, the direct functional mechanisms of tumor lethality mediated by apatinib have not yet been fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, in this study, we demonstrated that apatinib could induce both apoptosis and autophagy in human colorectal cancer (CRC) via a mechanism that involved endoplasmic reticulum (ER) stress. Moreover, activation of the IRE1α pathway from apatinib-induced ER stress is responsible for the induction of autophagy; however, blocking autophagy could enhance the apoptosis in apatinib-treated human CRC cell lines. Furthermore, the combination of apatinib with autophagy inhibitor chloroquine (CQ) tends to have the most significant anti-tumor effect of CRC both in vitro and in vivo. Overall, our data show that because apatinib treatment could induce ER stress-related apoptosis and protective autophagy in human CRC cell lines, targeting autophagy is a promising therapeutic strategy to relieve apatinib drug resistance in CRC.
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http://dx.doi.org/10.1016/j.canlet.2018.05.046DOI Listing
September 2018

CQ sensitizes human pancreatic cancer cells to gemcitabine through the lysosomal apoptotic pathway via reactive oxygen species.

Mol Oncol 2018 04 13;12(4):529-544. Epub 2018 Mar 13.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

As an established anticancer drug, gemcitabine (GEM) is an effective systemic treatment for advanced pancreatic cancer (PC). However, little is known about the potential effectors that may modify tumour cell sensitivity towards GEM. Autophagy, as a physiological cellular mechanism, is involved in both cell survival and cell death. In this study, we found that exposure to GEM induced a significant increase in autophagy in a dose-dependent manner in PANC-1 and BxPC-3 cells. Inhibition of autophagy by chloroquine (CQ) and ATG7 siRNA increased GEM-induced cytotoxicity, and CQ was more effective than ATG7 siRNA. Moreover, CQ significantly enhanced GEM-induced apoptosis, while ATG7 siRNA failed to show the similar effect. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that GEM with CQ pretreatment markedly triggered reactive oxygen species (ROS) boost and then increased lysosomal membrane permeability. Consequently, cathepsins released from lysosome into the cytoplasm induced apoptosis. We showed that CQ could enhance PC cells response to GEM in xenograft models. In conclusion, our data showed that CQ sensitized PC cells to GEM through the lysosomal apoptotic pathway via ROS. Thus, CQ as a potential adjuvant to GEM might represent an attractive therapeutic strategy for PC treatment.
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http://dx.doi.org/10.1002/1878-0261.12179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891043PMC
April 2018

Apatinib Inhibits Angiogenesis Via Suppressing Akt/GSK3β/ANG Signaling Pathway in Anaplastic Thyroid Cancer.

Cell Physiol Biochem 2017 1;44(4):1471-1484. Epub 2017 Dec 1.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background/aims: Anaplastic thyroid carcinoma (ATC) is one of the most lethal human malignancies, and there is no efficient method to slow its process. Apatinib, a novel tyrosine kinase inhibitor (TKI), has been confirmed for its efficacy and safety in the treatment of advanced gastric carcinoma patients. However, the effects of Apatinib in ATC are still unknown.

Methods: In this study, we explored the effects and mechanisms of Apatinib on tumor growth and angiogenesis in vitro and in vitro in ATC cells. Angiogenesis antibodies array was utilized to detect the expression of angiogenesis-related genes after Apatinib treatment in ATC cells. In addition, we used Akt activator, Akt inhibitor and GSK3β inhibitor to further study the mechanism for how Apatinib suppressed angiogenesis.

Results: Apatinib treatment could suppress the growth of ATC cells in a dose- and time-dependent manner via inducing apoptosis and blocking cell cycle progression at G0/G1 phase. Moreover, Apatinib treatment decreased the expression of angiogenin (ANG) and inhibited angiogenesis of ATC cells in vitro and in vitro. We further confirmed that recombinant human ANG (rhANG) significantly abrogated Apatinib-mediated anti-angiogenic ability in ATC cells. Additionally, Apatinib treatment decreased the level of p-Akt and p-GSK3β. Moreover, the Apatinib-mediated decrease of ANG and anti-angiogenic ability were partly reversed when an Akt activator, SC79, was administered. Furthermore, the anti-angiogenic ability of Apatinib can be enhanced in the presence of Akt inhibitor, and the inhibition of GSK3β attenuated the anti-angiogenic ability of Apatinib.

Conclusion: Our results demonstrated that Apatinib treatment inhibited tumor growth, and Apatinib-induced suppression of Akt/GSK3β/ANG signaling pathway may play an important role in the inhibition of angiogenesis in ATC, supporting a potential therapeutic approach for using Apatinib in the treatment of ATC.
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http://dx.doi.org/10.1159/000485583DOI Listing
January 2018
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