Publications by authors named "Weiliang Xia"

122 Publications

Knockdown of CDK5 down-regulates PD-L1 via the ubiquitination-proteasome pathway and improves antitumor immunity in lung adenocarcinoma.

Transl Oncol 2021 Sep 12;14(9):101148. Epub 2021 Jun 12.

Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 Huaihai West Road, Shanghai 200030, PR China. Electronic address:

Although immunotherapy (anti-PD-1/PD-L1 antibodies) has been approved for clinical treatment of lung cancer, only a small proportion of patients respond to monotherapy. Hence, understanding the regulatory mechanism of PD-L1 is particularly important to identify optimal combinations. In this study, we found that inhibition of CDK5 induced by shRNA or CDK5 inhibitor leads to reduced expression of PD-L1 protein in human lung adenocarcinoma cells, while the mRNA level is not substantially altered. The PD-L1 protein degradation is mediated by E3 ligase TRIM21 via ubiquitination-proteasome pathway. Subsequently, we studied the function of CDK5/PD-L1 axis in LUAD. In vitro, the absence of CDK5 in mouse Lewis lung cancer cell (LLC) has no effect on cell proliferation. However, the attenuation of CDK5 or combined with anti-PD-L1 greatly suppresses tumor growth in LLC implanted mouse models in vivo. Disruption of CDK5 elicits a higher level of CD3, CD4 and CD8 T cells in spleens and lower PD-1 expression in CD4 and CD8 T cells. Our findings highlight a role for CDK5 in promoting antitumor immunity, which provide a potential therapeutic target for combined immunotherapy in LUAD.
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http://dx.doi.org/10.1016/j.tranon.2021.101148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215302PMC
September 2021

Clonal Evolution Dynamics in Primary and Metastatic Lesions of Pancreatic Neuroendocrine Neoplasms.

Front Med (Lausanne) 2021 5;8:620988. Epub 2021 May 5.

Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Data on inter-tumoral heterogeneity and clonal evolution of pancreatic neuroendocrine neoplasms (panNENs) with liver metastasis are limited. The aim of this study was to explore different patterns of clonal evolution of pancreatic neuroendocrine neoplasms with liver metastasis and the possible distinctive signaling pathways involved between G2 neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). Tumor tissues of five patients (10 samples) with pancreatic neuroendocrine neoplasms with synchronous liver metastasis were analyzed using next-generation sequencing. PyClone, Gene Ontology, and Reactome pathway enrichment analysis were also applied. Mutated genes varied in individuals, reflecting the inter-tumoral heterogeneity of panNENs. The distribution of subclones varied during tumor metastasis, and different clonal evolution patterns were revealed between NETs and NECs. Gene Ontology and Reactome analyses revealed that in both NETs and NECs, signaling pathways and biological processes shared similarities and differences in the primary and metastatic lesions. In addition, the signaling pathway features were different between NETs and NECs. In the primary lesions, epigenetic changes and post-transcriptional modifications participated in NETs, while FGFR signaling, EGFR signaling, and NTRK2 signaling were largely involved in NECs. Although DNA repair and TP53 regulation were both involved in the metastatic lesions, most of the signaling pathways and biological processes disrupted by the mutated genes were different. Our study revealed spatial inter-tumoral heterogeneity and temporal clonal evolution in PanNENs, providing potential therapeutic targets for further prospective clinical trials.
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http://dx.doi.org/10.3389/fmed.2021.620988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131504PMC
May 2021

Targeted inhibition of SIRT6 via engineered exosomes impairs tumorigenesis and metastasis in prostate cancer.

Theranostics 2021 26;11(13):6526-6541. Epub 2021 Apr 26.

State Key Laboratory of Oncogenes and Related Genes, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.

The treatment for metastatic castration-resistant prostate cancer patients remains a great challenge in the clinic and continuously demands discoveries of new targets and therapies. Here, we assess the function and therapeutic value of SIRT6 in metastatic castration-resistant prostate cancer. The expression of SIRT6 was examined in prostate cancer tissue microarray by immunohistochemistry staining. The functions of SIRT6 and underlying mechanisms were elucidated by and experiments. We also developed an efficient method to silence SIRT6 by aptamer-modified exosomes carrying small interfering RNA and tested the therapeutic effect in the xenograft mice models. SIRT6 expression is positively correlated with prostate cancer progression. Loss of SIRT6 significantly suppressed proliferation and metastasis of prostate cancer cell lines both and . SIRT6-driven prostate cancer displays activation of multiple cancer-related signaling pathways, especially the Notch pathway. Silencing SIRT6 by siRNA delivered through engineered exosomes inhibited tumor growth and metastasis. SIRT6 is identified as a driver and therapeutic target for metastatic prostate cancer in our findings, and inhibition of SIRT6 by engineered exosomes can serve as a promising therapeutic tool for clinical application.
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http://dx.doi.org/10.7150/thno.53886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120217PMC
July 2021

Downregulation of circ-TRPS1 suppressed prostatic cancer prognoses by regulating miR-124-3p/EZH2 axis-mediated stemness.

Am J Cancer Res 2020 1;10(12):4372-4385. Epub 2020 Dec 1.

Fudan Institute of Urology, Huashan Hospital, Fudan University Shanghai 200040, China.

Abnormal circular RNA (circRNA) expression correlates with human traits such as many kinds of cancers. Though circRNAs have links to cancer, they have less characterization in metastatic castration-resistant prostate cancer (PCa), which is main reason for PCa mortality. Therefore, high-throughput sequencing was used for selected circRNA profiles. The result showed that circ-TRPS1 was upregulated significantly in high-grade PCa tissues or cell lines. High circ-TRPS1 expression correlated to aggressive PCa phenotypes. Knockdown of circ-TRPS1 suppressed PCa proliferation and metastasis through targeting miR-124-3p/EZH2 axis-mediated stemness in PCa, which was validated by luciferase reporter assays. EZH2 overexpression or miR-124-3p inhibition reversed the inhibition of circ-TRPS1 silencing in PCa cell migration and proliferation by recovering stemness. In summary, data demonstrated that circ-TRPS1 suppressed PCa progression through functioning similar to a miR-124-3p sponge to enhance EZH2 expression and cancer stem-like cell differentiation. Thus, circ-TRPS1 might be a candidate target for PCa treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783764PMC
December 2020

Bioglass could increase cell membrane fluidity with ion products to develop its bioactivity.

Cell Prolif 2020 Nov 11;53(11):e12906. Epub 2020 Oct 11.

School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.

Objectives: Silicate bioactive glass (BG) has been widely demonstrated to stimulate both of the hard and soft tissue regeneration, in which ion products released from BG play important roles. However, the mechanism by which ion products act on cells on cells is unclear.

Materials And Methods: Human umbilical vein endothelial cells and human bone marrow stromal cells were used in this study. Fluorescence recovery after photobleaching and generalized polarization was used to characterize changes in cell membrane fluidity. Migration, differentiation and apoptosis experiments were carried out. RNA and protein chip were detected. The signal cascade is simulated to evaluate the effect of increased cell membrane fluidity on signal transduction.

Results: We have demonstrated that ion products released from BG could effectively enhance cell membrane fluidity in a direct and physical way, and Si ions may play a major role. Bioactivities of BG ion products on cells, such as migration and differentiation, were regulated by membrane fluidity. Furthermore, we have proved that BG ion products could promote apoptosis of injured cells based on our conclusion that BG ion products increased membrane fluidity.

Conclusions: This study proved that BG ion products could develop its bioactivity on cells by directly enhancing cell membrane fluidity and subsequently affected cell behaviours, which may provide an explanation for the general bioactivities of silicate material.
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http://dx.doi.org/10.1111/cpr.12906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653244PMC
November 2020

PRKAR2B-HIF-1α loop promotes aerobic glycolysis and tumour growth in prostate cancer.

Cell Prolif 2020 Nov 7;53(11):e12918. Epub 2020 Oct 7.

Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Objectives: Reprogramming of cellular metabolism is profoundly implicated in tumorigenesis and can be exploited to cancer treatment. Cancer cells are known for their propensity to use glucose-dependent glycolytic pathway instead of mitochondrial oxidative phosphorylation for energy generation even in the presence of oxygen, a phenomenon known as Warburg effect. The type II beta regulatory subunit of protein kinase A (PKA), PRKAR2B, is highly expressed in castration-resistant prostate cancer (CRPC) and contributes to tumour growth and metastasis. However, whether PRKAR2B regulates glucose metabolism in prostate cancer remains largely unknown.

Materials And Methods: Loss-of-function and gain-of-function studies were used to investigate the regulatory role of PRKAR2B in aerobic glycolysis. Real-time qPCR, Western blotting, luciferase reporter assay and chromatin immunoprecipitation were employed to determine the underlying mechanisms.

Results: PRKAR2B was sufficient to enhance the Warburg effect as demonstrated by glucose consumption, lactate production and extracellular acidification rate. Mechanistically, loss-of-function and gain-of-function studies showed that PRKAR2B was critically involved in the tumour growth of prostate cancer. PRKAR2B was able to increase the expression level of hypoxia-inducible factor 1α (HIF-1α), which is a key mediator of the Warburg effect. Moreover, we uncovered that HIF-1α is a key transcription factor responsible for inducing PRKAR2B expression in prostate cancer. Importantly, inhibition of glycolysis by the glycolytic inhibitor 2-deoxy-d-glucose (2-DG) or replacement of glucose in the culture medium with galactose (which has a much lower rate than glucose entry into glycolysis) largely compromised PRKAR2B-mediated tumour-promoting effect. Similar phenomenon was noticed by genetic silencing of HIF-1α.

Conclusions: Our study identified that PRKAR2B-HIF-1α loop enhances the Warburg effect to enable growth advantage in prostate cancer.
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http://dx.doi.org/10.1111/cpr.12918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653268PMC
November 2020

Comparison of serum exosome isolation methods on co-precipitated free microRNAs.

PeerJ 2020 28;8:e9434. Epub 2020 Aug 28.

School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.

Background: Exosomes are nano-sized extracellular vesicles containing different biomolecules such as proteins and microRNAs (miRNAs) that mediate intercellular communication. Recently, numerous studies have reported the important functions of exosomal miRNAs in disease development and the potential clinical application as diagnostic biomarkers. Up to now, the most commonly used methods to extract exosomes are ultracentrifugation (UC) and precipitation-based commercial kit (e.g., ExoQuick). Generally, both UC and ExoQuick method could co-isolate contaminating proteins along with exosomes, with the UC method yielding even purer exosomes than ExoQuick. However, the comparison of these two methods on co-precipitated free miRNAs is still unknown.

Methods: In this study, we isolated exosomes from the human serum with exogenously added cel-miR-39 by UC and ExoQuick and compared the proportion of cel-miR-39 co-precipitated with exosomes extracted by these two methods.

Results: Using exogenous cel-miR-39 as free miRNAs in serum, we concluded that ExoQuick co-isolates a small proportion of free miRNAs while UC hardly precipitates any free miRNAs. We also found that incubation at 37 °C for 1 h could decrease the proportion of free miRNAs, and exosomal miRNAs like miR-126 and miR-152 also decreased when RNase A was used. In conclusion, our findings provide essential information about the details of serum exosome isolation methods for further research on exosomal miRNAs.
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http://dx.doi.org/10.7717/peerj.9434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457927PMC
August 2020

Correction: FGFR1-ERK1/2-SOX2 axis promotes cell proliferation, epithelial-mesenchymal transition, and metastasis in FGFR1-amplified lung cancer.

Oncogene 2020 Oct;39(42):6619-6620

Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, West Huaihai Road 241, Shanghai, 200030, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41388-020-01441-6DOI Listing
October 2020

PAK5 promotes the cell stemness ability by phosphorylating SOX2 in lung squamous cell carcinomas.

Exp Cell Res 2020 10 25;395(2):112187. Epub 2020 Jul 25.

Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, West Huaihai Road 241, 20030, Shanghai, China. Electronic address:

Growing evidences suggest that the overexpression of p21-activated kinase 5 (PAK5) plays an important role in various tumor progression. However, the role of PAK5 and its downstream target gene(s) in lung squamous cell carcinomas (LUSC) are waiting to be elucidated. TCGA data were utilized to evaluate the expression levels of PAK5 in LUSC. We then explored the role of PAK5 in maintaining the stem-like phenotype of lung squamous cancer cells through RT-PCR, flow cytometry, oncosphere-forming assay. In addition, co-immunoprecipitation, western blotting and immunofluorescence assays were used to determine SOX2 as a novel effector of PAK5. Xenograft models in nude mice were established to explore the roles of PAK5 in lung cancer growth. In this study, we have shown that PAK5 is overexpressed in LUSC tissues. The absence of PAK5 abolishes self-renewal ability of LUSC cells by decreasing the expression and phosphorylation of SOX2 in vitro and in vivo. In xenograft models, knockdown or pharmacological inhibition of PAK5 suppressed the tumor growth and metastasis of lung squamous cancer cells in vivo. Taken together, our findings suggest that the PAK5-mediated SOX2 phosphorylation promoted the cancer stem cell-like phenotype of LUSC cells. PAK5 inhibition may be a promising target in the treatment of SOX2 positive lung squamous cell cancer.
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http://dx.doi.org/10.1016/j.yexcr.2020.112187DOI Listing
October 2020

Sirt3 Protects Against Ischemic Stroke Injury by Regulating HIF-1α/VEGF Signaling and Blood-Brain Barrier Integrity.

Cell Mol Neurobiol 2021 Aug 4;41(6):1203-1215. Epub 2020 Jun 4.

School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.

Sirtuin 3 (Sirt3) is a member of the Sirtuin family proteins and known to regulate multiple physiological processes such as metabolism and aging. As stroke is an aging-related disease, in this work, we attempt to examine the role and potential mechanism of Sirt3 in regulating ischemic stroke by using a permanent middle cerebral artery occlusion (pMCAO) model in wild type (WT) and Sirt3 knockout (KO) mice, coupled with oxygen glucose deprivation (OGD) experiments in cultured primary astrocytes. Sirt3 deficiency aggravated neuronal cell apoptosis and neurological deficits after brain ischemia. In addition, Sirt3 KO mice showed more severe blood-brain barrier (BBB) disruption and inflammatory responses compared with WT group in the acute phase. Furthermore, specific overexpression of Sirt3 in astrocytes by injecting glial fibrillary acidic protein (GFAP)::Sirt3 virus in ischemic region showed protective effect against stroke-induced damage. Mechanistically, Sirt3 could regulate vascular endothelial growth factor (VEGF) expression by inhibiting hypoxia inducible factor-1α (HIF-1α) signaling after ischemia (OGD). Our results have shown that Sirt3 plays a protective role in ischemic stroke via regulating HIF-1α/VEGF signaling in astrocytes, and reversal of the Sirt3 expression at the acute phase could be a worthy direction for stroke therapy.
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http://dx.doi.org/10.1007/s10571-020-00889-0DOI Listing
August 2021

Slc26a3 deletion alters pH-microclimate, mucin biosynthesis, microbiome composition and increases the TNFα expression in murine colon.

Acta Physiol (Oxf) 2020 10 20;230(2):e13498. Epub 2020 Jun 20.

Department of Gastroenterology, Hannover Medical School, Hannover, Germany.

Aim: SLC26A3 (DRA) mediates the absorption of luminal Cl in exchange for HCO in the distal intestine. Its expression is lost in congenital chloride diarrhoea (CLD) and strongly decreased in the presence of intestinal inflammation. To characterize the consequences of a loss of Slc26a3 beyond disturbed electrolyte transport, colonic mucus synthesis, surface accumulation and composition, pH microclimate, microbiome composition and development of inflammation was studied in slc26a3 mice.

Methods: The epithelial surface pH microclimate and the surface mucus accumulation in vivo was assessed by two photon microscopy in exteriorized mid colon of anaesthetized slc26a3 and wt littermates. Mucus synthesis, composition and inflammatory markers were studied by qPCR and immunohistochemistry and microbiome composition by 16S rRNA sequencing.

Results: Colonic pH microclimate was significantly more acidic in slc26a3 and to a lesser extent in cftr than in wt mice. Goblet cell thecae per crypt were decreased in slc26a3 and increased in cftr colon. Mucus accumulation in vivo was reduced, but much less so than in cftr colon, which is possibly related to the different colonic fluid balance. Slc26a3 colonic luminal microbiome displayed strong decrease in diversity. These alterations preceded and maybe causally related to increased mucosal TNFα mRNA expression levels and leucocyte infiltration in the mid-distal colon of slc26a3 but not of cftr mice.

Conclusions: These findings may explain the strong increase in the susceptibility of slc26a3 mice to DSS damage, and offer insight into the mechanisms leading to an increased incidence of intestinal inflammation in CLD patients.
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http://dx.doi.org/10.1111/apha.13498DOI Listing
October 2020

Erratum: βKlotho is identified as a target for theranostics in non-small cell lung cancer: Erratum.

Theranostics 2020;10(12):5528-5529. Epub 2020 Apr 12.

State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.

[This corrects the article DOI: 10.7150/thno.35582.].
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http://dx.doi.org/10.7150/thno.46029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196295PMC
April 2020

Enhanced autocrine FGF19/FGFR4 signaling drives the progression of lung squamous cell carcinoma, which responds to mTOR inhibitor AZD2104.

Oncogene 2020 04 28;39(17):3507-3521. Epub 2020 Feb 28.

State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.

Lung cancer occurrence and associated mortality ranks top in all countries. Despite the rapid development of targeted and immune therapies, many patients experience relapse within a few years. It is urgent to uncover the mechanisms that drive lung cancer progression and identify novel molecular targets. Our group has previously identified FGF19 as a prognostic marker and potential driver gene of lung squamous cell carcinomas (LSQ) in Chinese smoking patients. However, the underlying mechanism of how FGF19 promotes the progression of LSQ remains unclear. In this study, we characterized and confirmed that FGF19 serves as an oncogenic driver in LSQ development and progression, and reported that the amplification and high expression of FGF19 in LSQ was significantly associated with poor overall and progression-free survival. A higher serum level of FGF19 was found in lung cancer patients, which could also serve as a novel diagnostic index to screen lung cancer. Overproduction of FGF19 in LSQ cells markedly promoted cell growth, progression and metastasis, while downregulating FGF19 effectively inhibited LSQ progression in vitro and in vivo. Moreover, downregulating the receptor FGFR4 was also effective to suppress the growth and migration of LSQ cells. Since FGF19 could be induced by smoking or endoplasmic reticulum stress, to tackle the more malignant FGF19-overproducing LSQ, we reported for the first time that inhibiting mTOR pathway by using AZD2014 was effective and feasible. These findings have offered a new strategy by using anti-FGF19/FGFR4 therapy or mTOR-based therapy in FGF19-driven LSQ.
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http://dx.doi.org/10.1038/s41388-020-1227-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176586PMC
April 2020

Transcriptional regulation of PRKAR2B by miR-200b-3p/200c-3p and XBP1 in human prostate cancer.

Biomed Pharmacother 2020 Apr 24;124:109863. Epub 2020 Jan 24.

Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China. Electronic address:

The cyclic adenosine monophosphate (cAMP)-activated protein kinase A (PKA) pathway is profoundly implicated in Prostate cancer (PCa) progression. Previously, we showed that PRKAR2B, the type II-beta regulatory subunit of PKA, is highly expressed in castration-resistant prostate cancer (CRPC) and can induce epithelial-mesenchymal transition by activating Wnt/β-catenin signaling in PCa cells. However, the molecular mechanism of dysregulated PRKAR2B expression pattern is still largely unknown. In this study, we found that the mutation, copy number alteration, and methylation status of PRKAR2B gene have no correlation with its expression level in PCa. Then, we identified two microRNAs (miR-200b-3p and miR-200c-3p) to be critical regulators of PRKAR2B expression in PCa. Notably, miR-200b-3p and miR-200c-3p expression were significantly downregulated in metastatic CRPC and negatively correlated with the expression level of PRKAR2B in PCa tissues. Moreover, we characterized X-Box Binding Protein 1 (XBP1) as a key transcription factor responsible for PRKAR2B expression in PCa. Importantly, miR-200b-3p/200c-3p or XBP1 knockdown inhibited PCa cell proliferation and promoted cell apoptosis and these inhibitory roles could be largely restored by PRKAR2B, suggesting that PRKAR2B is a functional mediator of miR-200b-3p, miR-200c-3p, and XBP1 in PCa. Collectively, our study firstly identified miR-200b-3p/200c-3p and XBP1 as the critical upstream regulators of PRKAR2B in PCa and provided novel insights to PRKAR2B-driven PCa progression.
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http://dx.doi.org/10.1016/j.biopha.2020.109863DOI Listing
April 2020

βKlotho is identified as a target for theranostics in non-small cell lung cancer.

Theranostics 2019 12;9(25):7474-7489. Epub 2019 Oct 12.

State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.

Non-small cell lung cancer (NSCLC) remains a great challenge, calling for the identification of novel molecular targets with diagnostic/therapeutic value. Here, we sought to characterize the expression of βKlotho and its anti-tumor roles in NSCLC. The expression of βKlotho was examined in NSCLC cells and tissues by western blot, qRT-PCR and immunohistochemistry staining respectively. Biological roles of βKlotho were revealed by a series of functional and studies. Serum βKlotho concentrations of patients were measured using specific ELISA methods. Serum βKlotho concentrations of NSCLC patients were significantly lower than the control group. Moreover, βKlotho expression was negatively associated with lymph node metastasis, overall survival and progression-free survival. Overexpression of βKlotho or exogenous βKlotho administration inhibited the proliferation and migration of NSCLC cells, accompanied by induction of apoptosis, G1 to S phase arrest, and inactivation of ERK1/2, AKT and STAT3 signaling. Furthermore, βKlotho overexpression inhibited NSCLC tumor growth . βKlotho serves as a novel target for theranostics in NSCLC, which has potential clinical applications in the future.
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http://dx.doi.org/10.7150/thno.35582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831461PMC
September 2020

Reciprocal regulatory mechanism between miR-214-3p and FGFR1 in FGFR1-amplified lung cancer.

Oncogenesis 2019 Sep 6;8(9):50. Epub 2019 Sep 6.

Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, West Huaihai Road 241, 20030, Shanghai, China.

MicroRNA (miRNA) and fibroblast growth factor receptor 1 (FGFR1) dysregulation are considered to play an important role in tumor proliferation, invasion, and metastasis. However, the regulatory mechanism between miRNAs and FGFR1 in lung cancer remains unclear and extremely critical. miR-214-3p was sharply decreased and showed a significantly negative correlation with FGFR1 in lung cancer patients (n = 30). Luciferase reporter assay confirmed that miR-214-3p could downregulate FGFR1 by directly targeting 3'-untranslated region (UTR). miR-214-3p inhibited the processes of epithelial-mesenchymal transition and Wnt/MAPK/AKT (Wnt/mitogen-activated protein kinase/AKT) signaling pathway by targeting FGFR1. Moreover, miR-214-3p not only established a negative feedback regulation loop with FGFR1 through ERK (extracellular signal-regulated kinase) but also developed a synergism with FGFR1 inhibitor AZD4547. In conclusion, our study demonstrated the regulatory mechanism between miR-214-3p and FGFR1 in lung cancer. miR-214-3p acts as a vital target in FGFR1-amplified lung cancer by forming a miR-214-3p-FGFR1-Wnt/MAPK/AKT signaling pathway network. Co-targeting miR-214-3p and FGFR1 could provide greater benefits to patients with FGFR1-amplified lung cancer.
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http://dx.doi.org/10.1038/s41389-019-0151-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731303PMC
September 2019

Upregulated KDM4B promotes prostate cancer cell proliferation by activating autophagy.

J Cell Physiol 2020 03 29;235(3):2129-2138. Epub 2019 Aug 29.

Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.

Castration-resistant prostate cancer (CRPC) causes most of the deaths in patients with prostate cancer (PCa). The androgen receptor (AR) axis plays an important role in castration resistance. Emerging studies showed that the lysine demethylase KDM4B is a key molecule in AR signaling and turnover, and autophagy plays an important role in CRPC. However, little is known about whether KDM4B promotes CRPC progression by regulating autophagy. Here we used an androgen-independent LNCaP (LNCaP-AI) cell line to assay aberrant KDM4B expression using qPCR and western blot analysis and investigated the function of KDM4B in regulating cell proliferation. We found that KDM4B was markedly increased in LNCaP-AI cells compared with LNCaP cells. KDM4B level was significantly correlated with the Gleason score in PCa tissues. In vitro, KDM4B overexpression in CRPC cells promoted cell proliferation, whereas knockdown of KDM4B significantly inhibited cell proliferation. Upregulated KDM4B contributed to activate Wnt/β-catenin signaling and autophagy. Moreover, KDM4B activated autophagy by regulating the Wnt/β-catenin signaling. Finally, we demonstrated that autophagy inhibition attenuated KDM4B-induced CRPC cell proliferation. Our results provided novel insights into the function of KDM4B-driven CRPC development and indicated that KDM4B may be served as a potential target for CRPC therapy.
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http://dx.doi.org/10.1002/jcp.29117DOI Listing
March 2020

Quick synthesis of a novel combinatorial delivery system of siRNA and doxorubicin for a synergistic anticancer effect.

Int J Nanomedicine 2019 15;14:3557-3569. Epub 2019 May 15.

Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, People's Republic of China.

Combining siRNA and other chemotherapeutic agents into one nanocarrier can overcome the multidrug resistance (MDR) phenomenon by synergistically MDR relative genes silencing and elevated chemotherapeutic activity. Most of these systems are typically fabricated through complicated procedures, which involves materials preparation, drug loading and modifications. Herein, the purpose of this study is to develop a new and fast co-delivery system of siRNA and doxorubicin for potentially synergistic cancer treatment. The co-delivery system is constructed conveniently by a stable complex consisting of doxorubicin bound to siRNA via intercalation firstly, followed by interacting with (3-Aminopropyl)triethoxysilane (APTES) electrostatically and Tetraethyl orthosilicate (TEOS) co-condensed, and the characterizations of the resultant nanocarrier are also investigated. Furthermore, this study evaluates the synergistic anti-cancer efficacy in MCF-7/MDR cells after treatment of siRNA and doxorubicin 'two in one' nanocarriers. We establish a new and fast method to craft a co-delivery system of siRNA and doxorubicin with controllable and nearly uniform size, and the entire fabrication process only costs in about 10 minutes. The resultant co-delivery system presents high loading capacities of siRNA and doxorubicin, and the encapsulated doxorubicin plays a pH-responsive control release. Further, biological functionality tests of the synthesized co-delivery nanocarriers show high inhibition of P-gp protein encoded by MDR-1 gene in MCF-7/MDR cells (a variant of human breast cancer cell line with drug resistance) after transfection of these nanocarriers carrying MDR-1 siRNA and doxorubicin simultaneously, which sensitize the MCF-7/MDR cells to doxorubicin, overall leading to improved cell suppression. Collectively, this co-delivery system not only serves as potent therapeutics for synergistic cancer therapy, it also may facilitate the bench-to-bedside translation of combinatorial delivery system as a robust drug nanocarrier by allowing for fabricating a simply and fast nanocarrier for co-delivery of siRNA and doxorubicin with predictable high production rate.
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http://dx.doi.org/10.2147/IJN.S198511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526930PMC
August 2019

Regulation of exosomes secretion by low-intensity pulsed ultrasound in lung cancer cells.

Exp Cell Res 2019 10 29;383(1):111448. Epub 2019 May 29.

School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Huashan Road 1954, Shanghai, 200030, China. Electronic address:

Low-intensity pulsed ultrasound (LIPUS) is a noninvasive therapeutic method which gradually being used in clinic including cancers. Exosomes mediate intercellular communication functions in disease development and the potential clinical applications in diagnosis and therapy. However, few studies have discussed the relationship between LIPUS and exosomes. Herein, we show that low intensity (0.6-2.1 W/cm or 0.6-3.4 W/cm) LIPUS promoted exosomes secretion whereas higher intensity (3.4-5.0 W/cm or 5.0 W/cm) LIPUS inhibited exosomes secretion, and this phenomenon is associated with autophagy. Pretreatment with 3-MA or down-regulation of LC3 potentiated low intensity LIPUS's promotion of exosomes secretion and conferred resistance to higher intensity LIPUS's effects on exosomes secretion. Furthermore, pretreatment with PP242 attenuated LIPUS-influenced exosomes secretion while expression of constitutively active Akt (Ad-myr-Akt) elevated LIPUS-influenced exosomes secretion, implying mTOR-dependent mechanism involved. The findings indicate that LIPUS influences exosomes secretion by targeting mTOR-mediated LC3 signaling in SPC-A1 and SPC-A1-BM cells. Our data provided initial evidence to connect LIPUS and secretion of exosomes, and highlight that LIPUS may be exploited in exosome-related diseases.
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http://dx.doi.org/10.1016/j.yexcr.2019.05.029DOI Listing
October 2019

Exosomal miR-499a-5p promotes cell proliferation, migration and EMT via mTOR signaling pathway in lung adenocarcinoma.

Exp Cell Res 2019 06 10;379(2):203-213. Epub 2019 Apr 10.

Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, West Huaihai Road 241, Shanghai, 200030, China. Electronic address:

Tumor-derived exosomes contain informative microRNAs involved in carcinogenesis, cell migration, invasion and epithelial-mesenchymal transition (EMT), eventually contributing to metastasis of cancers. This study aims to clarify which and how exosomal miRNA affects tumor carcinogenesis and metastasis. Among them, miR-499a-5p was upregulated in both highly metastatic lung cancer cell line and their exosomes. MiR-499a-5p overexpression promoted cell proliferation, migration and EMT, while miR-499a-5p knockdown suppressed these processes in vitro. Inhibition of miR-499a-5p by antagomirs administration restrained tumor growth in vivo. Consequently, miR499a-sufficient exosomes, derived from highly metastatic cell line, enhanced cell proliferation, migration and EMT via mTOR pathway, and the effect could be inhibited by miR-499a-5p inhibitor. The study reveals the potential diagnostic and therapeutic value of cancer-derived exosomal miR-499a-5p, and sheds a new insight on a novel molecular mechanism which modulates metastasis.
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http://dx.doi.org/10.1016/j.yexcr.2019.03.035DOI Listing
June 2019

Zeb1 is important for proper cleavage plane orientation of dividing progenitors and neuronal migration in the mouse neocortex.

Cell Death Differ 2019 Nov 11;26(11):2479-2492. Epub 2019 Mar 11.

State Key Laboratory of Oncogenes and Related Genes, Ren Ji Hospital, School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China.

During neocortical development, there are two important events, including expansion of the neural progenitor pool through symmetric divisions, and generation of neurons via asymmetrical divisions that lead to a serial process of neuronal polarization, migration, and layer-type specific phenotype acquisition. The mechanisms underlying these processes remain poorly elucidated. Here, we show that the transcription factor Zeb1 regulates the orientation of the cleavage plane of dividing neural progenitors, neuronal polarity, and migration. Upon Zeb1 removal, the cleavage plane of mitotic neural progenitors fails to orientate vertically, resulting in random orientation and premature neuronal differentiation. Consequently, these extra number of precociously produced neurons migrate aberrantly to the upper layer. Mechanistically, we show that Zeb1 suppresses Pak3, a p21-activated serine/threonine protein kinase, through formation of a functional repressing complex together with methyltransferase PRMT5 and Pak3. Our results reveal that Zeb1 plays an essential role in neocortical development and may provide insights into the mechanisms responsible for cortical developmental diseases.
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http://dx.doi.org/10.1038/s41418-019-0314-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889155PMC
November 2019

Adjudin synergizes with paclitaxel and inhibits cell growth and metastasis by regulating the sirtuin 3-Forkhead box O3a axis in human small-cell lung cancer.

Thorac Cancer 2019 04 18;10(4):642-658. Epub 2019 Feb 18.

Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Background: Small-cell lung cancer (SCLC), a malignant tumor, is usually widely metastatic when diagnosed. The lack of important therapeutic clinical advances makes it difficult to treat. Previous studies showed that Adjudin had anticancer effects in many other human cancers, and it was synergetic with cisplatin in non-small cell lung cancer. However, the mechanism on SCLC was unclear.

Methods: We investigated the potential mechanism and effect of Adjudin on SCLC both in vitro and in vivo.

Results: An SCLC xenograft model showed that Adjudin inhibited tumor growth and was significantly synergetic with paclitaxel (in vitro as well). Cell Counting Kit-8 assays, flow cytometric analysis and western blotting showed that Adjudin effectively suppressed SCLC cell proliferation by inducing S phase arrest and caspase-dependent apoptosis. Moreover, Transwell and scratch assays showed that Adjudin also effectively inhibited migration and invasion. Furthermore, Adjudin activated the sirtuin 3 (SIRT3)-Forkhead box O3a (FOXO3a) pathway. Downregulating SIRT3 or FOXO3a significantly attenuated Adjudin-induced anticancer effects. Furthermore, higher expression of SIRT3 and FOXO3a were positively correlated, and both were associated with longer survival in lung cancer patients.

Conclusion: Overall, the present study is the first to show that Adjudin synergizes with paclitaxel and inhibits cell growth and metastasis by regulating the SIRT3-FOXO3a axis in SCLC; thus, Adjudin has great potential to be an anticancer agent.
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http://dx.doi.org/10.1111/1759-7714.12976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449276PMC
April 2019

An Invasive Hemolymphangioma of the Pancreas in a Young Woman.

Comb Chem High Throughput Screen 2018 ;21(10):798-800

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.

Background: Hemolymphangioma is a rare benign tumor. To the best of our knowledge, there were only 10 reports of this tumor of the pancreas until March 2018.

Case Report: Here, we reported a large invasive hemolymphangioma of the pancreas in a young woman with a complaint of abdominal distension and an epigastric mass about 3 weeks. She was found to have a huge multilocular cystic tumor at the neck and body of pancreas on computed tomography. She was eventually diagnosed with hemolymphangioma of the pancreas after operation. After 2 years of follow-up, there was no signs of recurrence.

Conclusion: From our case and literature, we can conclude that hemolymphangioma of the pancreas is uncommon benign tumor, and it is hard to make an accurate diagnosis preoperatively. Radical surgical resection should be performed whenever possible. The prognosis of this disease seems good.
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http://dx.doi.org/10.2174/1386207322666190103110747DOI Listing
July 2019

Structural basis for ligand recognition of the human thromboxane A receptor.

Nat Chem Biol 2019 01 3;15(1):27-33. Epub 2018 Dec 3.

CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Stimulated by thromboxane A, an endogenous arachidonic acid metabolite, the thromboxane A receptor (TP) plays a pivotal role in cardiovascular homeostasis, and thus is considered as an important drug target for cardiovascular disease. Here, we report crystal structures of the human TP bound to two nonprostanoid antagonists, ramatroban and daltroban, at 2.5 Å and 3.0 Å resolution, respectively. The TP structures reveal a ligand-binding pocket capped by two layers of extracellular loops that are stabilized by two disulfide bonds, limiting ligand access from the extracellular milieu. These structures provide details of interactions between the receptor and antagonists, which help to integrate previous mutagenesis and SAR data. Molecular docking of prostanoid-like ligands, combined with mutagenesis, ligand-binding and functional assays, suggests a prostanoid binding mode that may also be adopted by other prostanoid receptors. These insights into TP deepen our understanding about ligand recognition and selectivity mechanisms of this physiologically important receptor.
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http://dx.doi.org/10.1038/s41589-018-0170-9DOI Listing
January 2019

Adjudin delays cellular senescence through Sirt3‑mediated attenuation of ROS production.

Int J Mol Med 2018 Dec 8;42(6):3522-3529. Epub 2018 Oct 8.

State Key Laboratory of Oncogenes and Related Genes, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.

Aging, marked by the physical and functional decline in numerous biological processes, is associated with multiple pathologies including cancer, neurodegenerative diseases and cardiocerebral vascular diseases. The accumulation of reactive oxygen species (ROS) production is considered one of the major causes of aging‑associated diseases and a major therapeutic target. Hydroxyurea has been widely used for cellular senescence model. The expression level of cell cycle-related protein, ROS production and senescence-associated β-galactosidase are considered to be markers of cellular senescence. Strategies to slow senescence may be beneficial for various aging‑associated diseases. The results of the current study indicated that adjudin, a multi‑functional small molecule compound, delayed hydroxyurea‑induced senescence in mouse embryo fibroblasts (MEFs). Adjudin reduced the proportion of senescence‑associated β‑galactosidase‑positive cells and decreased the expression levels of senescence‑associated markers, p16 and p21. Mechanistically, adjudin exerted its anti‑senescence effect by elevating the expression level of sirtuin 3 (Sirt3), which attenuated ROS production through the regulation of forkhead box O3a and manganese superoxide dismutase expression. Furthermore, by comparing wild‑type and Sirt3‑knockout MEFs, it was demonstrated that Sirt3 mediated the anti‑senescence effect of adjudin. Taken together, the findings indicated that adjudin has anti‑aging properties that may be exploited to treat aging‑associated diseases.
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http://dx.doi.org/10.3892/ijmm.2018.3917DOI Listing
December 2018

FGFR1-ERK1/2-SOX2 axis promotes cell proliferation, epithelial-mesenchymal transition, and metastasis in FGFR1-amplified lung cancer.

Oncogene 2018 09 1;37(39):5340-5354. Epub 2018 Jun 1.

Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, West Huaihai Road 241, Shanghai, 200030, China.

Epithelial-mesenchymal transition (EMT) is an important process for cancer metastasis, drug resistance, and cancer stem cells. Activation of fibroblast growth factor receptor 1 (FGFR1) was found to promote EMT and metastasis in prostate and breast cancers, but the effects and mechanisms in lung cancer was unclear. In this study, we aimed to explore whether and how activation of FGFR1 promotes EMT and metastasis in FGFR1-amplified lung cancer. We show that activation of FGFR1 by its ligand fibroblast growth factor 2 (FGF2) promoted proliferation, EMT, migration, and invasion in FGFR1-amplified lung cancer cell lines H1581 and DMS114, whereas inhibition of FGFR1 suppressed these processes. FGFR1 activation upregulated expression of Sry-related HMG box 2 (SOX2) by downstream phosphorylated ERK1/2; moreover, the upregulation of SOX2 by autophosphorylation variant ERK2_R67S plasmid transfection was not suppressed by FGFR1 inhibitor AZD4547 or MEK/ERK inhibitor AZD6244 in vitro. And SOX2 expression was also significantly upregulated in ERK2_R67S lentivirus-transfected stable cell lines in vivo. Overexpression of SOX2 promoted cell proliferation, EMT, migration, and invasion. Importantly, activation of FGFR1 could not promote these processes in SOX2-silenced stable cell lines. In orthotopic and subcutaneous lung cancer xenograft models, inhibition of FGFR1 suppressed tumor growth, SOX2 expression, EMT, and metastasis in vivo; however, these processes caused by SOX2-overexpressing stable cell lines were not suppressed by FGFR1 inhibition. Higher expression of FGFR1 and SOX2 were positively correlated, and both were associated with shorter survival in lung cancer patients. In conclusion, our findings reveal that activation of FGFR1 promotes cell proliferation, EMT, and metastasis by the newly defined FGFR1-ERK1/2-SOX2 axis in FGFR1-amplified lung cancer.
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http://dx.doi.org/10.1038/s41388-018-0311-3DOI Listing
September 2018

PRKAR2B promotes prostate cancer metastasis by activating Wnt/β-catenin and inducing epithelial-mesenchymal transition.

J Cell Biochem 2018 09 15;119(9):7319-7327. Epub 2018 May 15.

Department of Urology, RenJi Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People's Republic of China.

Castration-resistant prostate cancers (CRPC) that occur after the failure of androgen-blocking therapies cause most of the deaths in prostate cancer (PCa) patients. In a previous study we identified that PRKAR2B expression is upregulated in CRPC and possesses potentials to develop CRPC. Here we further investigated the underlying mechanism of PRKAR2B in regulating prostate cancer metastasis. We established an androgen-independent LNCaPcell line (LNCaP-AI), and investigated the function of PRKAR2B on regulating cell invasion in vitro and in vivo. We found that PRKAR2B expression was markedly increased in LNCaP-AI cells and metastatic CRPC (mCRPC) tissues compared to LNCaP cells and primary PCa specimens, respectively. PRKAR2B level was significantly correlated with the Gleason score and lymph nodes metastasis in PCa. In vitro, PRKAR2B overexpression promoted cell invasion, whereas knockdown of PRKAR2B in CRPC cells inhibited cell invasion. PRKAR2B overexpression also promoted tumor metastasis in vivo. PRKAR2B resulted in a decreased expression of E-cadherin and an increased expression of Vimentin, N-cadherin, Fibronectin, indicating that PRKAR2B induced epithelial-mesenchymal transition (EMT). PRKAR2B activated Wnt/β-catenin signaling in CRPC cells. More important, inhibition of Wnt/β-catenin attenuated PRKAR2B-induced EMT and cancer cells invasion. Our results provided novel insights to PRKAR2B-driven CRPC cell invasion and indicated that PRKAR2B might be served as a potential target for CRPC therapy.
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http://dx.doi.org/10.1002/jcb.27030DOI Listing
September 2018

Corrigendum to "The Hippo/YAP1 pathway interacts with FGFR1 signaling to maintain stemness in lung cancer" [Canc. Lett. 423 (2018) 36-46].

Cancer Lett 2018 Sep 10;431:244. Epub 2018 May 10.

Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, PR China. Electronic address:

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http://dx.doi.org/10.1016/j.canlet.2018.04.014DOI Listing
September 2018

Effect of pH, temperature and freezing-thawing on quantity changes and cellular uptake of exosomes.

Protein Cell 2019 04;10(4):295-299

School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China.

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http://dx.doi.org/10.1007/s13238-018-0529-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418301PMC
April 2019

The Hippo/YAP1 pathway interacts with FGFR1 signaling to maintain stemness in lung cancer.

Cancer Lett 2018 06 13;423:36-46. Epub 2018 Feb 13.

Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, PR China. Electronic address:

The Hippo pathway plays a critical role in organ size control, tissue homeostasis and tumor genesis through its key transcription regulator Yes-associated protein1 (YAP1), but the mechanism underlying its role in lung cancer is unclear. We hypothesized that YAP1 influences FGFR1 signaling to maintain cancer stem-like cell (CSC) properties in FGFR1-amplified lung cancer. In support of this, our data confirms that expression levels of YAP1 are positively associated with those of FGFR1 in clinical lung carcinoma samples as measured by real-time PCR, western blot, and immunohistochemistry (IHC) staining. Mechanistically, YAP1 up-regulates FGFR1 expression at the level of promoter through the TEAD binding site while bFGF/FGFR1 induces YAP1 expression via large tumor suppressors 1(LATS1). In addition, the absence of YAP1 abolishes self-renewal ability in lung cancer. Furthermore, an orthotropic mouse model highlights the function of YAP1 in the initiation and metastasis of lung cancer. Verteporfin, a YAP1 inhibitor, effectively inhibits both YAP1 and FGFR1 expression in lung cancer. Thus, we conclude that YAP1 is a potential therapeutic target for lung cancer. Combined targeting of YAP1 and FGFR1 may provide benefits to patients with FGFR1-amplified lung cancer.
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http://dx.doi.org/10.1016/j.canlet.2018.02.015DOI Listing
June 2018
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