Publications by authors named "Lunquan Sun"

60 Publications

Dvl2 facilitates the coordination of NF-κB and Wnt signaling to promote colitis-associated colorectal progression.

Cancer Sci 2021 Nov 22. Epub 2021 Nov 22.

Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.

Colitis-associated colorectal cancer (CAC) arises due to prolonged inflammation and has distinct molecular events compared to sporadic colorectal cancer (CRC). Although inflammatory NF-κB signaling was activated by proinflammatory cytokines (such as TNFα) in early-stage of CAC, Wnt/β-catenin signaling later appears to function as a key regulator of CAC progression. However, the exact mechanism responsible for the cross-regulation between these two pathways remains unclear. Here, we found reciprocal inhibition between NF-κB and Wnt/β-catenin signalings in CAC samples, and the Dvl2, an adaptor protein of Wnt/β-catenin signaling, is responsible for NF-κB inhibition. Mechanistically, Dvl2 interacts with the C-terminus of TNFRI and mediates TNFRI endocytosis, leading to NF-κB signal inhibition. In addition, increased infiltration of the pro-inflammatory cytokine interleukin-13 (IL-13) is responsible for upregulating Dvl2 expression through STAT6. Targeting STAT6 effectively decreases Dvl2 level and restrains colony formation of cancer cells. These findings demonstrate a unique role for Dvl2 in TNFRI endocytosis, which facilitates the coordination of NF-κB and Wnt to promote CAC progression.
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http://dx.doi.org/10.1111/cas.15206DOI Listing
November 2021

The protein kinase activity of NME7 activates Wnt/β-Catenin signaling to promote one-carbon metabolism in hepatocellular carcinoma.

Cancer Res 2021 Nov 11. Epub 2021 Nov 11.

Xiangya Cancer Center, Xiangya Hospital, Central South University.

Metabolic reprogramming by oncogenic signaling is a hallmark of cancer. Hyperactivation of Wnt/β-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the mechanisms inducing hyperactivation of Wnt/β-catenin signaling and strategies for targeting this pathway are incompletely understood. In this study, we find nucleoside diphosphate kinase 7 (NME7) to be a positive regulator of Wnt/β-catenin signaling. Upregulation of NME7 positively correlated with the clinical features of HCC. Knockdown of NME7 inhibited HCC growth in vitro and in vivo, while overexpression of NME7 cooperated with c-Myc to drive tumorigenesis in a mouse model and promote the growth of tumor-derived organoids. Mechanistically, NME7 bound and phosphorylated serine 9 of GSK3β to promote β-catenin activation. Furthermore, MTHFD2, the key enzyme in one-carbon metabolism, was a target gene of β-catenin and mediated the effects of NME7. Tumor-derived organoids with NME7 overexpression exhibited increased sensitivity to MTHFD2 inhibition. Additionally, expression levels of NME7, β-catenin and MTHFD2 correlated with each other and with poor prognosis in HCC patients. Collectively, this study emphasizes the crucial roles of NME7 protein kinase activity in promoting Wnt/β-catenin signaling and one-carbon metabolism, suggesting NME7 and MTHFD2 as potential therapeutic targets for HCC.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-1020DOI Listing
November 2021

Lung cancer-associated T cell repertoire as potential biomarker for early detection of stage I lung cancer.

Lung Cancer 2021 Sep 28;162:16-22. Epub 2021 Sep 28.

Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, China; Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, China; Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Changsha, China. Electronic address:

Background: Early detection of lung cancer in asymptomatic patients remains challenging, especially for stage I. Considering the substantial interaction with tumor immunogenicity, we hypothesized that lung cancer-associated TCR (LC-aTCR) may serve as potential biomarker in early detection of stage I lung cancer.

Methods: Individuals who received low-dose computed tomography (LDCT) screening were enrolled in the study. Surgical tissues and peripheral blood specimens were collected and performed with DNA-based T cell repertoire (TCR) sequencing. The motif-based algorithm was used to deconstruct specific lung cancer-associated TCRs (LC-aTCRs).

Results: A total of 146 individuals participating in the real-world LDCT screening project were enrolled in this study, including 52 patients with pathologically-confirmed stage I lung cancer and 94 non-cancer controls. We developed a motif-based algorithm to define 80 LC-aTCRs in the training cohort. Moreover, in the validation cohort, high sensitivity and specificity was showed in stage I lung cancer with 72% and 91% respectively, and the AUC of the ROC curve was 0.91 (95% CI: 0.85 ∼ 0.96).

Conclusion: This work provides inspiration for stage I lung cancer detection by using blood TCR profiling data. The combination of TCR-based assay and routine screening deserves further testing in larger cohorts.
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http://dx.doi.org/10.1016/j.lungcan.2021.09.017DOI Listing
September 2021

Suppression of DLBCL Progression by the E3 Ligase Trim35 Is Mediated by CLOCK Degradation and NK Cell Infiltration.

J Immunol Res 2021 24;2021:9995869. Epub 2021 May 24.

Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, China.

The majority of diffuse large B-cell lymphoma (DLBCL) patients develop relapsed or refractory disease after standard ruxolitinib, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, which is partly related to a dysregulated tumor immune microenvironment. However, how the infiltration of immune cells is appropriately regulated is poorly understood. Herein, we show that the E3 ubiquitin ligase Trim35 is expressed at low levels in human DLBCL tissues. We also show that overexpression of Trim35 suppresses DLBCL cell proliferation and correlates with inferior survival in DLBCL patients. Our mechanistic study shows that Trim35 functions as an E3 ligase to mediate the ubiquitination and degradation of CLOCK, a key regulator of circadian rhythmicity. High expression of Trim35 correlates with NK cell infiltration in DLBCL, partly due to the degradation of CLOCK. Consistently, patients with high expression of CLOCK show poor overall survival. Overall, these findings suggest that Trim35 suppresses the progression of DLBCL by modulating the tumor immune microenvironment, indicating that it may be a promising diagnostic and prognostic biomarker in DLBCL.
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http://dx.doi.org/10.1155/2021/9995869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166485PMC
May 2021

A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea.

EMBO Mol Med 2021 05 18;13(5):e13560. Epub 2021 Mar 18.

Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.

Rosacea is a chronic inflammatory skin disorder whose pathogenesis is unclear. Here, several lines of evidence were provided to demonstrate that mTORC1 signaling is hyperactivated in the skin, especially in the epidermis, of both rosacea patients and a mouse model of rosacea-like skin inflammation. Both mTORC1 deletion in epithelium and inhibition by its specific inhibitors can block the development of rosacea-like skin inflammation in LL37-induced rosacea-like mouse model. Conversely, hyperactivation of mTORC1 signaling aggravated rosacea-like features. Mechanistically, mTORC1 regulates cathelicidin through a positive feedback loop, in which cathelicidin LL37 activates mTORC1 signaling by binding to Toll-like receptor 2 (TLR2) and thus in turn increases the expression of cathelicidin itself in keratinocytes. Moreover, excess cathelicidin LL37 induces both NF-κB activation and disease-characteristic cytokine and chemokine production possibly via mTORC1 signaling. Topical application of rapamycin improved clinical symptoms in rosacea patients, suggesting mTORC1 inhibition can serve as a novel therapeutic avenue for rosacea.
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http://dx.doi.org/10.15252/emmm.202013560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103105PMC
May 2021

Defective Viral Particles Produced in Mast Cells Can Effectively Fight Against Lethal Influenza A Virus.

Front Microbiol 2020 4;11:553274. Epub 2020 Nov 4.

Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China.

Mast cells play an important role in the pathogenesis of highly pathogenic H5N1 avian influenza virus (H5N1-HPAIV) infection. Defective viral particles (DPs) can interfere with the replication of infectious viruses and stimulate the innate immune response of host cells. However, DPs arising from mast cells during HPAIV replication and their potent antiviral actions has not been reported. Here, we showed that the human mastocytoma cell line, HMC-1, allowed for the productive replication of the H5N1-HPAIV. Compared with alveolar cell line A549, DPs were propagated preferentially and abundantly in mast cells following IAV infection, which can be attributed to the wide existence of Argonaute 2 (AGO2) in HMC-1 cells. In addition, DPs generated in H5N1-infected cells could provide great therapeutic protection on mice to fight against various influenza A viruses, which included not only homologous H5N1-HPAIV, but also heterologous H1N1, H3N2, H7N2, and H9N2. Importantly, DPs generated in H5N1-infected HMC-1 cells could diminish viral virulence and by triggering a robust antiviral response through type II interferon signaling pathways. This study is the first to illustrate the arising of DPs in H5N1-HPAIV infected mast cells and explore their favorable ability to protect mice from influenza A viruses infection, which provides a novel insight and valuable information for the progress of new strategies to fight influenza A viruses infection, especially highly pathogenic avian influenza virus infection by focusing on the DPs generated in mast cells.
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http://dx.doi.org/10.3389/fmicb.2020.553274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671969PMC
November 2020

CDK11 negatively regulates Wnt/β-catenin signaling in the endosomal compartment by affecting microtubule stability.

Cancer Biol Med 2020 05;17(2):328-342

Department of Oncology, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.

Improper activation of Wnt/β-catenin signaling has been implicated in human diseases. Beyond the well-studied glycogen synthase kinase 3β (GSK3β) and casein kinase 1 (CK1), other kinases affecting Wnt/β-catenin signaling remain to be defined. To identify the kinases that modulate Wnt/β-catenin signaling, we applied a kinase small interfering RNA (siRNA) library screen approach. Luciferase assays, immunoblotting, and real-time polymerase chain reaction (PCR) were performed to confirm the regulation of the Wnt/β-catenin signaling pathway by cyclin-dependent kinase 11 (CDK11) and to investigate the underlying mechanism. Confocal immunofluorescence, coimmunoprecipitation (co-IP), and scratch wound assays were used to demonstrate colocalization, detect protein interactions, and explore the function of CDK11. CDK11 was found to be a significant candidate kinase participating in the negative control of Wnt/β-catenin signaling. Down-regulation of CDK11 led to the accumulation of Wnt/β-catenin signaling receptor complexes, in a manner dependent on intact adenomatosis polyposis coli (APC) protein. Further analysis showed that CDK11 modulation of Wnt/β-catenin signaling engaged the endolysosomal machinery, and CDK11 knockdown enhanced the colocalization of Wnt/β-catenin signaling receptor complexes with early endosomes and decreased colocalization with lysosomes. Mechanistically, CDK11 was found to function in Wnt/β-catenin signaling by regulating microtubule stability. Depletion of CDK11 down-regulated acetyl-α-tubulin. Moreover, co-IP assays demonstrated that CDK11 interacts with the α-tubulin deacetylase SIRT2, whereas SIRT2 down-regulation in CDK11-depleted cells reversed the accumulation of Wnt/β-catenin signaling receptor complexes. CDK11 was found to suppress cell migration through altered Wnt/β-catenin signaling. CDK11 is a negative modulator of Wnt/β-catenin signaling that stabilizes microtubules, thus resulting in the dysregulation of receptor complex trafficking from early endosomes to lysosomes.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2019.0229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309457PMC
May 2020

ADORA1 Inhibition Promotes Tumor Immune Evasion by Regulating the ATF3-PD-L1 Axis.

Cancer Cell 2020 03;37(3):324-339.e8

Department of Dermatology, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, Hunan 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan 410008, China; Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, Hunan 410008, China. Electronic address:

Here, we show that tumor ADORA1 deletion suppresses cell growth in human melanoma cell lines in vitro and tumor development in vivo in immune-deficient xenografts. However, this deletion induces the upregulation of PD-L1 levels, which inactivates cocultured T cells in vitro, compromises anti-tumor immunity in vivo, and reduces anti-tumor efficacy in an immune-competent mouse model. Functionally, PD-1 mAb treatment enhances the efficacy of ADORA1-deficient or ADORA1 antagonist-treated melanoma and NSCLC immune-competent mouse models. Mechanistically, we identify ATF3 as the factor transcriptionally upregulating PD-L1 expression. Tumor ATF3 deletion improves the effect of ADORA1 antagonist treatment of melanoma and NSCLC xenografts. We observe higher ADORA1, lower ATF3, and lower PD-L1 expression levels in tumor tissues from nonresponders among PD-1 mAb-treated NSCLC patients.
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http://dx.doi.org/10.1016/j.ccell.2020.02.006DOI Listing
March 2020

Corrigendum: SCD1 Confers Temozolomide Resistance to Human Glioma Cells Akt/GSK3β/β-Catenin Signaling Axis.

Front Pharmacol 2019;10:1358. Epub 2019 Nov 15.

Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.

[This corrects the article DOI: 10.3389/fphar.2017.00960.].
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http://dx.doi.org/10.3389/fphar.2019.01358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874015PMC
November 2019

Novel Function of lncRNA ADAMTS9-AS2 in Promoting Temozolomide Resistance in Glioblastoma via Upregulating the FUS/MDM2 Ubiquitination Axis.

Front Cell Dev Biol 2019 2;7:217. Epub 2019 Oct 2.

Key Laboratory for Molecular Radiation Oncology of Hunan Province, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.

Background: LncRNAs have been shown to play essential roles in cancer therapeutic response. However, the detailed mechanism of lncRNAs in temozolomide (TMZ) resistance in glioblastoma (GBM) remain to be elucidated.

Methods: To elucidate the mechanism maintaining TMZ resistance, we constructed two TMZ-resistant GBM cell lines (T98G-R/U118-R). LncRNAs from four public datasets were reanalyzed, and the candidate lncRNA ADAMTS9-AS2 was evaluated in TMZ-treated GBM patients and cell lines.

Results: Reanalysis of lncRNA expression profiles identified ADAMTS9-AS2 as significantly overexpressed in TMZ-resistant GBM cells and as positively associated with the IC of TMZ in GBM cells. Overexpression of ADAMTS9-AS2 was also significantly associated with poor TMZ response and shorter progression-free survival (PFS) in TMZ-treated GBM patients. Knockdown of ADAMTS9-AS2 inhibited proliferation and attenuated the IC of TMZ, as well as mitigating invasion and migration in TMZ-resistant GBM cells. Subsequent investigations indicated that reduced expression of ADAMTS9-AS2 significantly suppressed expression of the FUS protein, which was predicted as a direct substrate of ADAMTS9-AS2. Expression trends of FUS were directly correlated with those of ADAMTS9-AS2, as shown by increasing concentrations and prolonged treatment with TMZ. RNA pull-down and RIP assays indicated that both endogenous and exogenous ADAMTS9-AS2 directly binds to the RRM and Znf_RanBP2 domains of FUS, consequently increasing FUS protein expression. Knockdown of ADAMTS9-AS2 reduced the half-life of FUS and decreased FUS protein stability via K48 ubiquitin degradation. Moreover, the E3 ubiquitin-protein ligase MDM2 interacts with and down regulates FUS, while the RRM and Znf_RanBP2 domains of FUS facilitate its binding with MDM2. ADAMTS9-AS2 decreased the interaction between MDM2 and FUS, which mediates FUS K48 ubiquitination. Additionally, knockdown of the ADAMTS9-AS2/FUS signaling axis significantly alleviated progression and metastasis in TMZ-resistant cells.

Conclusion: ADAMTS9-AS2 possessed a novel function that promotes TMZ resistance via upregulating the FUS/MDM2 axis in GBM cells. The RRM or Znf_RanBP2 domains of FUS facilitate the combination of ADAMTS9-AS2 and FUS, competitively inhibiting MDM2-dependent FUS K48 ubiquitination and resulting in enhanced FUS stability and TMZ resistance. Our results suggest that the ADAMTS9-AS2/FUS/MDM2 axis may represent a suitable prognostic biomarker and a potential target in TMZ-resistant GBM therapy.
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http://dx.doi.org/10.3389/fcell.2019.00217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783494PMC
October 2019

p-STAT1 regulates the influenza A virus replication and inflammatory response in vitro and vivo.

Virology 2019 11 25;537:110-120. Epub 2019 Aug 25.

Key Laboratory of Animal Epidemiology of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China. Electronic address:

Influenza A virus infection activates various intracellular signaling pathways, which is mediated by the transcription factors. Here, a quantitative phosphoproteomic analysis of A549 cells after infection with influenza A virus (H5N1) was performed and we found that the transcription factor STAT1 was highly activated. Unexpectedly, upon inhibition of p-STAT1, titers of progeny virus and viral protein synthesis were both reduced. The STAT1 inhibitor Fludarabine (FLUD) inhibited an early progeny step in viral infection and reduced the levels of influenza virus genomic RNA (vRNA). Concomitantly, there was reduced expression of inflammatory cytokines in p-STAT1 inhibited cells. In vivo, suppression of p-STAT1 improved the survival of H5N1 virus-infected mice, reduced the pulmonary inflammatory response and viral burden. Thus, our data demonstrated a critical role for p-STAT1 in influenza virus replication and inflammatory responses. We speculate that STAT1 is an example of a putative antiviral signaling component to support effective replication.
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http://dx.doi.org/10.1016/j.virol.2019.08.023DOI Listing
November 2019

Oestrogen dose tapering during luteal phase does not affect clinical outcomes after hormone replacement treatment-frozen-thawed embryo transfer cycles: a retrospective analysis.

Hum Reprod 2019 08;34(8):1479-1484

Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.

Study Question: Does oestrogen dose tapering during the luteal phase affect the clinical outcome after hormone replacement treatment-frozen-thawed embryo transfer (HRT-FET) cycles?

Summary Answer: Our results suggest that tapering oestrogen doses during the luteal phase results in similar clinical outcomes to those obtained with the traditional luteal phase support (LPS).

What Is Known Already: Traditional LPS with oestrogen and progesterone is considered necessary in HRT-FET cycles. However, case reports have shown successful clinical pregnancies and live births in the absence of oestrogen administration after embryo transfers.

Study Design, Size, Duration: This was a retrospective study on 6035 HRT-FET cycles extending over 7 years from January 2011 to June 2018 at the reproductive medicine centre of Xiangya Hospital.

Participants/materials, Setting, Methods: We compared the clinical outcomes of 1632 HRT-FET cycles with tapered oestrogen doses from 12 days after embryo transfer (study group) to those of 4403 HRT-FET cycles maintained on constant oestrogen doses during the luteal phase (control group) in the case of positive serum HCG test.

Main Results And The Role Of Chance: We found similar biochemical pregnancy rates (52.1% vs. 51.9, P = 0.864), clinical pregnancy rates (44.9% vs. 43.2%, P = 0.249), implantation rates (29.8% vs. 29.3%, P = 0.591) and miscarriage rates (16.0% vs. 14.6%, P = 0.379) between the studied groups.

Limitations, Reasons For Caution: Retrospective, design-associated biases are possible. In addition, some baseline characteristics differed between groups. Finally, we did not compare live birth rates between groups.

Wider Implications Of The Findings: Our study showing similar outcomes between traditional LPS and oestrogen tapering during the luteal phase indicates that oestrogen may be cautiously tapered during the luteal phase after HRT-FET cycles.

Study Funding/competing Interest(s): This work was supported by the National Natural Science Foundation of China (grant no. 81401269) and the class General Financial Grant from the China Postdoctoral Science Foundation (grant no. 2017M620360). The authors declare that they have no competing interests.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/dez096DOI Listing
August 2019

MRI-Based Radiomics Predicts Tumor Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

Front Oncol 2019 26;9:552. Epub 2019 Jun 26.

Department of Diagnostic Radiology, City of Hope National Medical Center, Duarte, CA, United States.

Conventional methods for predicting treatment response to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) are limited. This study retrospectively recruited 134 LARC patients who underwent standard nCRT followed by total mesorectal excision surgery in our institution. Based on pre-operative axial T2-weighted images, machine learning radiomics was performed. A receiver operating characteristic (ROC) curve was performed to test the efficiencies of the predictive model. Among the 134 patients, 32 (23.9%) achieved pathological complete response (pCR), 69 (51.5%) achieved a good response, and 91 (67.9%) achieved down-staging. For prediction of pCR, good-response, and down-staging, the predictive model demonstrated high classification efficiencies, with an AUC value of 0.91 (95% CI: 0.83-0.98), 0.90 (95% CI: 0.83-0.97), and 0.93 (95% CI: 0.87-0.98), respectively. Our machine learning radiomics model showed promise for predicting response to nCRT in patients with LARC. Our predictive model based on the commonly used T2-weighted images on pelvic Magnetic Resonance Imaging (MRI) scans has the potential to be adapted in clinical practice. Methods for predicting the response of the locally advanced rectal cancer (LARC, T3-4, or N+) to neoadjuvant chemoradiotherapy (nCRT) is lacking. In the present study, we developed a new machine learning radiomics method based on T2-weighted images. As a non-invasive tool, this method facilitates prediction performance effectively. It achieves a satisfactory overall diagnostic accuracy for predicting of pCR, good response, and down-staging show an AUC of 0.908, 0.902, and 0.930 in LARC patients, respectively.
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http://dx.doi.org/10.3389/fonc.2019.00552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606732PMC
June 2019

The HBx-CTTN interaction promotes cell proliferation and migration of hepatocellular carcinoma via CREB1.

Cell Death Dis 2019 05 28;10(6):405. Epub 2019 May 28.

Department of Infectious Diseases and Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China.

Hepatitis B virus-encoded X protein (HBx) acts as a tumor promoter during hepatocellular carcinoma (HCC) development, probably by regulating the expression of host proteins through protein-protein interaction. A proteomics approach was used to identify HBx-interacting proteins involved in HBx-induced hepatocarcinogenesis. We validated the proteomics findings by co-immunoprecipitation and confocal microscopy. We performed cell proliferation, migration assays and cell cycle analyses in HCC cells. Finally, we confirmed the clinical significance of our findings in samples from patients. We found that cortactin (CTTN) is a novel HBx-interacting protein, and HBx regulates the expression of CTTN in the HCC cell lines MHCC-LM3 and HepG2. Mechanistically, by upregulating the expression of cAMP response element-binding protein (CREB1) and its downstream targets, such as cyclin D1 and MMP-9, the effects of the HBx-CTTN interaction on the enhancement of cellular proliferation and migration were maintained by inhibiting cell cycle arrest. In addition, we demonstrated that the levels of CTTN and CREB1 were closely correlated in clinical samples from HBV-infected patients with HCC. Overall, our data suggests that HBx contributes to cell migration and proliferation of HCC cells by interacting with CTTN and regulating the expression of CTTN and CREB1. Therefore, the HBx/CTTN/CREB1 axis is a potential novel therapeutic target in HCC.
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http://dx.doi.org/10.1038/s41419-019-1650-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538608PMC
May 2019

The effects and the mechanisms of autophagy on the cancer-associated fibroblasts in cancer.

J Exp Clin Cancer Res 2019 Apr 23;38(1):171. Epub 2019 Apr 23.

Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.

Cancer-associated fibroblasts (CAFs) plays an essential role in cancer cell growth, metabolism and immunoreaction. Autophagy is an intracellular self-degradative process that balances cell energy source and regulates tissue homeostasis. Targeting autophagy has gained interest with multiple preclinical and clinical trials, such as the pharmacological inhibitor chloroquine or the inducer rapamycin, especially in exploiting its ability to modulate the secretory capability of CAFs to enhance drug delivery or inhibit it to prevent its influence on cancer cell chemoresistance. In this review, we summarize the reports on autophagy in cancer-associated fibroblasts by detailing the mechanism and role of autophagy in CAFs, including the hypoxic-autophagy positive feedback cycle, the metabolic cross-talk between CAFs and tumors induced by autophagy, CAFs secreted cytokines promote cancer survival by secretory autophagy, CAFs autophagy-induced EMT, stemness, senescence and treatment sensitivity, as well as the research of antitumor chemicals, miRNAs and lncRNAs. Additionally, we discuss the evidence of molecules in CAFs that are relevant to autophagy and the contribution to sensitive treatments as a potential target for cancer treatment.
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http://dx.doi.org/10.1186/s13046-019-1172-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480893PMC
April 2019

Dephosphorylation of Girdin by PP2A inhibits breast cancer metastasis.

Biochem Biophys Res Commun 2019 05 29;513(1):28-34. Epub 2019 Mar 29.

Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan. Electronic address:

Dysfunction of Girdin plays a crucial role in the development of a variety of tumors. Phosphorylated regulation of Girdin has been studied extensively. However, how Girdin is dephosphorylated remains unclear. In this study, we report a mechanism of Girdin dephosphorylation and the importance of this mechanism in the migration of breast cancer cells. We show that the protein phosphatase 2A (PP2A) complex can bind to Girdin via the modulating B subunit. Overexpression or knockdown of PP2A inhibits or increases the phosphorylation of Girdin at serine 1416, respectively. PP2Ac-induced Girdin dephosphorylation is involved in the inhibition of breast cancer cell migration. Furthermore, in human breast cancer samples, PP2Ac expression is negatively correlated with the phosphorylation of Girdin, and low expression of PP2Ac is correlated with tumor stage, grade and lymph node metastasis of breast cancer. These data indicate that PP2A regulates Girdin dephosphorylation and highlight the critical role of this pathway in breast cancer metastasis.
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http://dx.doi.org/10.1016/j.bbrc.2019.03.167DOI Listing
May 2019

Effect of Low-Intensity Pulsed Ultrasound After Autologous Adipose-Derived Stromal Cell Transplantation for Bone-Tendon Healing in a Rabbit Model.

Am J Sports Med 2019 03;47(4):942-953

Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.

Background: Low-intensity pulsed ultrasound (LIPUS), as a safe biophysiotherapy, can enhance bone-tendon (B-T) healing in vivo and induce osteogenic or chondrogenic differentiation of mesenchymal stromal cells in vitro. This study aimed to determine whether LIPUS can improve the efficacy of transplanted mesenchymal stromal cells on B-T healing.

Hypothesis: LIPUS can induce lineage-specific differentiation of transplanted adipose-derived stromal cells (ASCs) at the B-T healing site, thus resulting in superior healing quality when compared with LIPUS or ASCs alone.

Study Design: Controlled laboratory study.

Methods: A total of 112 mature rabbits with partial patellectomy in the hindlimb were randomly assigned into mock sonication without ASCs (control), ultrasonication without ASCs (LIPUS), mock sonication with ASCs (ASCs), and ultrasonication with ASCs (LIPUS + ASCs). The treatment time of the mock sonication or ultrasonication was 20 minutes per day. Autologous ASCs were transplanted to the healing site by fibrin glue during the operation, and LIPUS was delivered daily starting at postoperative day 3 until euthanasia. The patella-patellar tendon junctions were postoperatively harvested at 8 and 16 weeks for radiological, histological, and mechanical evaluations. Additionally, 9 animals were used for ASC tracking with mCherry protein.

Results: Radiologically, there was more new bone formation and remodeling in the LIPUS + ASCs group as compared with the other groups. Synchrotron radiation micro-computed tomography showed that the LIPUS + ASCs group significantly increased bone volume fraction, trabecular thickness, and trabecular number at the healing site as compared with the other groups at postoperative 8 weeks ( P < .05 for all). Histologically, immunohistochemical staining confirmed that the transplanted mCherry-ASCs can differentiate into osteoblasts and fibrochondrocytic-like cells. Meanwhile, as compared with the other groups, the LIPUS + ASCs group showed more formation and maturity of the fibrocartilage layer and new bone at postoperative weeks 8 and 16 ( P < .05 for all). Biomechanically, the LIPUS + ASCs group showed significantly higher failure load and stiffness versus the other groups at postoperative weeks 8 and 16 ( P < .05 for all).

Conclusion: Autologous ASC transplantation stimulated with LIPUS can result in superior B-T healing quality when compared with LIPUS or ASCs alone.

Clinical Relevance: This study demonstrates the effectiveness of using ASC transplantation stimulated with LIPUS for B-T healing and provides a foundation for future clinical studies.
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http://dx.doi.org/10.1177/0363546518820324DOI Listing
March 2019

Author Correction: Loss of Phd2 cooperates with BRAF to drive melanomagenesis.

Nat Commun 2019 03 11;10(1):1211. Epub 2019 Mar 11.

Center for Research on Reproduction & Women's Health, University of Pennsylvania, Philadelphia, PA, 19104, USA.

The original version of this Article contained an error in the spelling of the author Brett L. Ecker, which was incorrectly given as Brett Ecker. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-019-09195-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411891PMC
March 2019

Blastocoele expansion: an important parameter for predicting clinical success pregnancy after frozen-warmed blastocysts transfer.

Reprod Biol Endocrinol 2019 Jan 23;17(1):15. Epub 2019 Jan 23.

Reproductive Medicine Center, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha City, Hunan Province, People's Republic of China.

Objective: To assess the predictive value of each individual morphological parameter: blastocoele expansion degree, inner cell mass (ICM), and trophectoderm (TE) grades on the clinical pregnancy outcome in frozen-warmed embryo transfer (FET) cycles.

Methods: This is a retrospective cohort study, including 1154 FET cycles receiving vitrified-warmed one or two blastocysts transfer from August 2011 through to May 2018. The correlation between blastocyst morphology parameters and clinical outcome after FET was assessed.

Results: In the subgroup analysis based on clinical pregnancy, the patients who achieved clinical pregnancy had a significantly higher degree of blastocyst expansion (3.69 ± 0.68 vs. 3.53 ± 0.78, P = 0.000) and had a thicker endometrium (9.65 ± 1.63 vs. 9.28 ± 1.64) compared with those with non-clinical pregnancy. The logistic regression analysis showed that among the three blastocyst morphology parameters, only the blastocoele expansion degree was significantly correlated with the clinical pregnancy outcome and had ability to predict the outcome after FET cycles with one or two vitrified-warmed blastocysts transferred. Both ICM and TE stages were not associated with pregnancy outcomes.

Conclusions: The blastocoele expansion degree may be essential for successful pregnancy and should be given priority when selecting frozen blastocyst for transfer.
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http://dx.doi.org/10.1186/s12958-019-0454-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344998PMC
January 2019

Book-Shaped Acellular Fibrocartilage Scaffold with Cell-loading Capability and Chondrogenic Inducibility for Tissue-Engineered Fibrocartilage and Bone-Tendon Healing.

ACS Appl Mater Interfaces 2019 Jan 8;11(3):2891-2907. Epub 2019 Jan 8.

Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008.

Functional fibrocartilage regeneration is a bottleneck during bone-tendon healing, and the currently available tissue-engineering strategies for fibrocartilage regeneration are insufficient because of a lack of appropriate scaffold that can load large seeding-cells and induce chondrogenesis of stem cells. The acellular fibrocartilage scaffold (AFS) contains active growth factors as well as tissue-specific epitopes for cell-matrix interactions, which make it a potential scaffold for tissue-engineered fibrocartilage. A limitation to this scaffold is that its low porosity inhibits cells loading and infiltration. Here, inspired by book appearance, we sectioned native fibrocartilage tissue (NFT) into book-shape to improve cells loading and infiltration, and then decellularized with four protocols: (1) 2% SDS for 6-h, (2) 2% SDS for 24-h, (3) 4 SDS for 6-h, (4) 4% SDS for 24-h, followed by nuclease digestion. The optimal protocol was screened with respect to microstructures, DNA residence, native ingredients reservation, and chondrogenic inducibility of the AFS. In vitro studies demonstrated that this screened scaffold is noncytotoxicity and low-immunogenicity, allows adipose-derived stromal cells (ASCs) attachment and proliferation, shows superior chondrogenic inducibility, and stimulates collagen or glycosaminoglycans secretion. The underlying mechanism for this chondrogenic inducibility may be related to hedgehog pathway activating. Additionally, a novel pattern for fabricating tissue-engineered fibrocartilage was developed to enlarge seeding-cells loading, namely, cell-sheets sandwiched by book-shaped scaffold. In-vivo studies indicate that this screened scaffold alone could induce endogenous cells to satisfactorily regenerate fibrocartilage at 16-week, as characterized by fibrocartilaginous extracellular matrix (ECM) deposition and good interface integration. Interleaving this book-shaped AFS with autologous ASCs-sheets significantly enhanced its ability to regenerate fibrocartilage. Cell tracking demonstrated that fibrochondrocytes, osteoblasts, and osteocytes in the healing interface at postoperative 8-week partly originated from the sandwiched ASCs-sheets. On that basis, we propose the use of this book-shaped AFS and cell sheet technique for fabricating tissue-engineered fibrocartilage to improve bone-tendon healing.
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http://dx.doi.org/10.1021/acsami.8b20563DOI Listing
January 2019

Loss of Phd2 cooperates with BRAF to drive melanomagenesis.

Nat Commun 2018 12 21;9(1):5426. Epub 2018 Dec 21.

Center for Research on Reproduction & Women's Health, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Prolyl hydroxylase domain protein 2 (PHD2) is a well-known master oxygen sensor. However, the role of PHD2 in tumor initiation remains controversial. We find that during the transition of human nevi to melanoma, the expression of PHD2 protein is significantly decreased and lower expression PHD2 in melanoma is associated with worse clinical outcome. Knockdown of PHD2 leads to elevated Akt phosphorylation in human melanocytes. Mice with conditional melanocyte-specific expression of Phd2 (Tyr::CreER;Phd2) fail to develop pigmented lesions. However, deletion of Phd2 in combination with expression of BRaf in melanocytes (Tyr::CreER;Phd2;BRaf) leads to the development of melanoma with 100% penetrance and frequent lymph node metastasis. Analysis of tumor tissues using reverse phase protein arrays demonstrates that Phd2 deletion activates the AKT-mTOR-S6 signaling axis in the recovered tumors. These data indicate that PHD2 is capable of suppressing tumor initiation largely mediated through inhibiting of the Akt-mTOR signaling pathway in the melanocyte lineage.
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http://dx.doi.org/10.1038/s41467-018-07126-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303344PMC
December 2018

Radiation-promoted CDC6 protein stability contributes to radioresistance by regulating senescence and epithelial to mesenchymal transition.

Oncogene 2019 01 29;38(4):549-563. Epub 2018 Aug 29.

Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.

Ionizing radiation (IR) is a conventional cancer therapeutic, to which cancer cells develop radioresistance with exposure. The residual cancer cells after radiation treatment also have increased metastatic potential. The mechanisms by which cancer cells develop radioresistance and gain metastatic potential are still unknown. In this study acute IR exposure induced cancer cell senescence and apoptosis, but after long-term IR exposure, cancer cells exhibited radioresistance. The proliferation of radioresistant cells was retarded, and most cells were arrested in G0/G1 phase. The radioresistant cells simultaneously showed resistance to further IR-induced apoptosis, premature senescence, and epithelial to mesenchymal transformation (EMT). Acute IR exposure steadily elevated CDC6 protein levels due to the attenuation of ubiquitination, while CDC6 overexpression was observed in the radioresistant cells because the insufficiency of CDC6 phosphorylation blocked protein translocation from nucleus to cytoplasm, resulting in subcellular protein accumulation when the cells were arrested in G0/G1 phase. CDC6 ectopic overexpression in CNE2 cells resulted in apoptosis resistance, G0/G1 cell cycle arrest, premature senescence, and EMT, similar to the characteristics of radioresistant CNE2-R cells. Targeting CDC6 with siRNA promoted IR-induced senescence, sensitized cancer cells to IR-induced apoptosis, and reversed EMT. Furthermore, CDC6 depletion synergistically repressed the growth of CNE2-R xenografts when combined with IR. The study describes for the first time cell models for IR-induced senescence, apoptosis resistance, and EMT, three major mechanisms by which radioresistance develops. CDC6 is a novel radioresistance switch regulating senescence, apoptosis, and EMT. These studies suggest that CDC6KI67 represents a new diagnostic marker of radiosensitivity, and CDC6 represents a new therapeutic target for cancer radiosensitization.
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http://dx.doi.org/10.1038/s41388-018-0460-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345673PMC
January 2019

PARP inhibitor veliparib and HDAC inhibitor SAHA synergistically co-target the UHRF1/BRCA1 DNA damage repair complex in prostate cancer cells.

J Exp Clin Cancer Res 2018 Jul 16;37(1):153. Epub 2018 Jul 16.

Center for Molecular Medicine, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.

Background: The poly ADP ribose polymerase (PARP) inhibitor olaparib has been approved for treating prostate cancer (PCa) with BRCA mutations, and veliparib, another PARP inhibitor, is being tested in clinical trials. However, veliparib only showed a moderate anticancer effect, and combination therapy is required for PCa patients. Histone deacetylase (HDAC) inhibitors have been tested to improve the anticancer efficacy of PARP inhibitors for PCa cells, but the exact mechanisms are still elusive.

Methods: Several types of PCa cells and prostate epithelial cell line RWPE-1 were treated with veliparib or SAHA alone or in combination. Cell viability or clonogenicity was tested with violet crystal assay; cell apoptosis was detected with Annexin V-FITC/PI staining and flow cytometry, and the cleaved PARP was tested with western blot; DNA damage was evaluated by staining the cells with γH2AX antibody, and the DNA damage foci were observed with a fluorescent microscopy, and the level of γH2AX was tested with western blot; the protein levels of UHRF1 and BRCA1 were measured with western blot or cell immunofluorescent staining, and the interaction of UHRF1 and BRCA1 proteins was detected with co-immunoprecipitation when cells were treated with drugs. The antitumor effect of combinational therapy was validated in DU145 xenograft models.

Results: PCa cells showed different sensitivity to veliparib or SAHA. Co-administration of both drugs synergistically decreased cell viability and clonogenicity, and synergistically induced cell apoptosis and DNA damage, while had no detectable toxicity to normal prostate epithelial cells. Mechanistically, veliparib or SAHA alone reduced BRCA1 or UHRF1 protein levels, co-treatment with veliparib and SAHA synergistically reduced BRCA1 protein levels by targeting the UHRF1/BRCA1 protein complex, the depletion of UHRF1 resulted in the degradation of BRCA1 protein, while the elevation of UHRF1 impaired co-treatment-reduced BRCA1 protein levels. Co-administration of both drugs synergistically decreased the growth of xenografts.

Conclusions: Our studies revealed that the synergistic lethality of HDAC and PARP inhibitors resulted from promoting DNA damage and inhibiting HR DNA damage repair pathways, in particular targeting the UHRF1/BRCA1 protein complex. The synergistic lethality of veliparib and SAHA shows great potential for future PCa clinical trials.
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http://dx.doi.org/10.1186/s13046-018-0810-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048811PMC
July 2018

Gliosarcoma: a clinical and radiological analysis of 48 cases.

Eur Radiol 2019 Jan 12;29(1):429-438. Epub 2018 Jun 12.

Department of Neurosurgery, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, Hunan, 410008, People's Republic of China.

Objectives: To retrospectively review the radiological and clinicopathological features of gliosarcoma (GSM) and differentiate it from glioblastoma multiforme (GBM).

Methods: The clinicopathological data and imaging findings (including VASARI analysis) of 48 surgically and pathologically confirmed GSM patients (group 1) were reviewed in detail, and were compared with that of other glioblastoma (GBM) cases in our hospital (group 2).

Results: There were 28 men and 20 women GSM patients with a median age of 52.5 years (range, 24-80 years) in this study. Haemorrhage (n = 21), a salt-and-pepper sign on T2-weighted images (n = 36), unevenly thickened wall (n = 36) even appearing as a paliform pattern (n = 32), an intra-tumoural large feeding artery (n = 32) and an eccentric cystic portion (ECP) (n = 19) were more commonly observed in the GSM group than in GBM patients. Based on our experience, GSM can be divided into four subtypes according to magnetic resonance imaging (MRI) features. When compared to GBM (group 2), there were more patients designated with type III lesions (having very unevenly thickened walls) and IV (solid) lesions among the GSM cases (group 1). On univariate prognostic analysis, adjuvant therapy (radiotherapy, chemotherapy, and radiochemotherapy) and existence of an eccentric cyst region were prognostic factors. However, Cox's regression model showed only adjuvant therapy as a prognostic factor for GSM.

Conclusions: When compared to GBM, certain imaging features are more likely to occur in GSM, which may help raise the possibility of this disease. All GSM patients are recommended to receive adjuvant therapy to achieve a better prognosis with radiotherapy, chemotherapy or radiochemotherapy all as options.

Key Points: • Diagnosis of gliosarcoma can be suggested preoperatively by imaging. • Gliosarcoma can be divided into four subtypes based on MRI. • Paliform pattern and ECP tend to present in gliosarcoma more than GBM. • The cystic subtype of gliosarcoma may predict a more dismal prognosis. • All gliosarcoma patients should receive adjuvant therapy to achieve better prognosis.
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http://dx.doi.org/10.1007/s00330-018-5398-yDOI Listing
January 2019

Fibrosarcoma arising in the paranasal sinus: a clinicopathological and radiological analysis.

Dentomaxillofac Radiol 2018 Jul 23;47(6):20170459. Epub 2018 Apr 23.

1 Department of Radiology, Xiangya Hospital, Central South University , Changsha , China.

Objectives: To analyze the clinicopathological features and the CT and MRI features of patients with paranasal sinus fibrosarcoma.

Methods: Seven patients with surgically and pathologically confirmed paranasal sinus fibrosarcoma were enrolled. Their CT and MRI data and imaging features were retrospectively analyzed in detail.

Results: The study participants were two males and five females (median age, 43 years; range, 22-73 years). CT or MRI showed a well-defined (n = 5) or ill-defined (n = 2), irregular (n = 6) or oval (n = 1) mass, with heterogeneous (n = 7) density. The lesions were isointense (n = 4) or hypointense (n = 2) on T weighted images, and showed heterogeneous (n = 6) mild hypointensity on T weighted images. Expansive (n = 6) and osteolytic (n = 1) bone destruction were observed. The tumors showed marked heterogeneous delayed enhancement (n = 6) on contrast-enhanced MRI images.

Conclusion: Paranasal sinus fibrosarcomas should be included in the differential diagnosis when a sinonasal neoplasm appears as a well- or ill-defined unilateral large irregular mass with characteristic mild hypointensity on T weighted MR images and shows expansive or osteolytic bone destruction and a marked heterogeneous delayed contrast-enhancement pattern.
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http://dx.doi.org/10.1259/dmfr.20170459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196049PMC
July 2018

Ultraviolet A irradiation induces senescence in human dermal fibroblasts by down-regulating DNMT1 via ZEB1.

Aging (Albany NY) 2018 02;10(2):212-228

Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.

In this study, we report the role of DNA methyltransferase 1 (DNMT1) in ultraviolet A (UVA)-induced senescence in human dermal fibroblasts (HDFs). We show that DNMT1 expression was significantly reduced during UVA-induced senescence, and this senescence could be alleviated or aggravated by the up- or down-regulation of DNMT1, respectively. Expression of the transcription factor zinc finger E-box binding homeobox 1(ZEB1) also decreased after UVA irradiation, following a UVA-induced increase of intracellular reactive oxygen species (ROS). We show that ZEB1 binds to the DMNT1 promoter and regulates its transcription, which, in turn, affects cellular senescence. These changes in DMNT1 and ZEB1 expression following UVA exposure were confirmed in matched skin specimens that had or had not been sun-exposed. On analyzing the promoter methylation of 24 senescence associated genes in these matched skin specimens, we discovered that p53 promoter methylation was significantly reduced in sun-exposed skin. experiments confirmed that UVA irradiation reduced p53 promoter methylation, and DNMT1 up-regulation could reverse this effect. Collectively, down-regulation of ZEB1 caused by UVA induced ROS could transcriptionally inhibit DNMT1, leading to low methylation level of senescence related proteins p53 and increase its expression, eventually result in cellar senescence.
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http://dx.doi.org/10.18632/aging.101383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842848PMC
February 2018

SCD1 Confers Temozolomide Resistance to Human Glioma Cells via the Akt/GSK3β/β-Catenin Signaling Axis.

Front Pharmacol 2017 4;8:960. Epub 2018 Jan 4.

Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.

Resistance to temozolomide (TMZ), the standard chemotherapy agent for glioblastoma (GBM), poses a major clinical challenge to GBM prognosis. Understanding the mechanisms of TMZ resistance can help to identify novel drug targets and more effective therapies. Recent studies suggest that bioenergetic alterations of cancer cells play important roles in drug resistance. In our study, the altered metabolism of cancer cells was observed using a metabolic PCR array. We found that stearoyl-coenzyme A desaturase 1 (SCD1), a key rate-limiting enzyme for synthesis of monounsaturated fatty acids, was significantly upregulated in TMZ-resistant GBM cells compared to their parental counterparts. Overexpression of SCD1 promoted resistance to TMZ in parental GBM cells, whereas SCD1 downregulation by siRNA could re-sensitize TMZ-resistant cells . Combinational treatment of TMZ and an SCD1-specific inhibitor showed a combined inhibitory effect on TMZ-resistant glioma cells. We also observed that overexpression of SCD1 promoted Akt/GSK3β/β-catenin signaling, while silencing of SCD1 inhibited the signaling. The combination of an Akt activator with exogenous SCD1 or the combined inhibition of Akt and enforced expression of SCD1 resulted in the most significant changes of Akt signaling. Functionally, significantly lower viability and mobility rates were observed in TMZ-resistant cells when treated with Akt inhibitors and an SCD1 inhibitor simultaneously compared to when treated individually. In conclusion, our study identified SCD1 along with its functional pathway as a novel target in the development of TMZ resistance. SCD1 inhibition used alone or in combination with Akt inhibition could effectively overcome TMZ resistance in gliomas.
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http://dx.doi.org/10.3389/fphar.2017.00960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758607PMC
January 2018

Crosstalk between hepatitis B virus X and high-mobility group box 1 facilitates autophagy in hepatocytes.

Mol Oncol 2018 03 24;12(3):322-338. Epub 2018 Jan 24.

Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China.

Hepatitis B virus (HBV) X (HBx) protein is a pivotal regulator of HBV-triggered autophagy. However, the role of HBx-induced epigenetic changes in autophagy remains largely unknown. The cytoplasmic (Cyt) high-mobility group box 1 (HMGB1) has been identified as a positive regulator of autophagy, and its Cyt translocation is closely associated with its acetylation status. Here, we evaluated the function of HMGB1 in HBx-mediated autophagy and its association with histone deacetylase (HDAC). Using cell lines with enforced expression of HBx, we demonstrated that HBx upregulated the expression of HMGB1 and promoted its Cyt translocation by acetylation to facilitate autophagy. We further identified the underlying mechanism by which decreased nuclear HDAC activity and expression levels contribute to the HBx-promoted hyperacetylation and subsequent translocation of HMGB1. We also identified the HDAC1 isoform as a critical factor in regulating this phenomenon. In addition, HBx bound to HMGB1 in the cytoplasm, which triggered autophagy in hepatocytes. Pharmacological inhibition of HMGB1 Cyt translocation with ethyl pyruvate prevented HBx-induced autophagy. These results demonstrate a novel function of acetylated HMGB1 in HBx-mediated autophagy in hepatocytes.
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http://dx.doi.org/10.1002/1878-0261.12165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830655PMC
March 2018

High mobility group box 1 promotes sorafenib resistance in HepG2 cells and in vivo.

BMC Cancer 2017 Dec 15;17(1):857. Epub 2017 Dec 15.

Hunan Key Laboratory of Viral Hepatitis, Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China.

Background: Primary liver cancer is a lethal malignancy with a high mortality worldwide. Currently, sorafenib is the most effective molecular-targeted drug against hepatocellular carcinoma (HCC). However, the sorafenib resistance rate is high. The molecular mechanism of this resistance has not been fully elucidated. High mobility group box 1 (HMGB1) is a multifaceted protein that plays a key role in the proliferation, apoptosis, metastasis and angiogenesis of HCC cells. In addition, HMGB1 has been suggested to contribute to chemotherapy resistance in tumours, including lung cancer, osteosarcoma, neuroblastoma, leukaemia, and colorectal cancer. This study investigated the association between HMGB1 and sorafenib resistance in HCC.

Methods: HepG2 cells with HMGB1 knockdown or overexpression were generated. The efficacy of sorafenib in these cells was tested using flow cytometry and a cell counting assay. The subcellular localization of HMGB1 in HepG2 cells following sorafenib treatment was measured by western blotting and confocal microscopy. A murine subcutaneous HCC model was generated to examine the association between HMGB1 and the sensitivity of sorafenib treatment.

Results: The HMGB1 knockdown cells exhibited a significantly higher apoptotic level and lower cell viability than the normal HMGB1 expressing cells following the sorafenib treatment. In addition, the cell viability observed in the HMGB1 overexpressing cells was higher than that observed in the control cells following the sorafenib intervention. Sorafenib had a better tumour inhibition effect in the HMGB1 knockdown group in vivo. The amount of mitochondrial HMGB1 decreased, while the amount of cytosolic HMGB1 increased following the exposure to sorafenib. Altogether, HMGB1 translocated from the mitochondria to the cytoplasm outside the mitochondria following the exposure of HepG2 cells to sorafenib.

Conclusions: A novel potential role of HMGB1 in the regulation of sorafenib therapy resistance in HCC was observed. The knockdown of HMGB1 restores sensitivity to sorafenib and enhances HepG2 cell death, while HMGB1 overexpression blunts these effects. The translocation of HMGB1 from the mitochondria to the cytosol following sorafenib treatment provides new insight into sorafenib resistance in HCC.
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http://dx.doi.org/10.1186/s12885-017-3868-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731191PMC
December 2017

Spinal Solitary Fibrous Tumor/Hemangiopericytoma: A Clinicopathologic and Radiologic Analysis of Eleven Cases.

World Neurosurg 2017 Aug 13;104:318-329. Epub 2017 May 13.

Department of Ultrasonic Imaging, Xiangya Hospital, Central South University, Changsha, China. Electronic address:

Objective: To retrospectively review the clinicopathologic features and computed tomography (CT) and magnetic resonance imaging (MRI) findings of spinal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) tumors.

Methods: Eleven patients with surgically and pathologically confirmed spinal SFT/HPC were enrolled. Their clinicopathologic data and imaging findings were retrospectively reviewed.

Results: There were 8 male and 3 female patients with a median age of 42 years (range, 26-65 years). Of the 11 patients, 5 were classified as grade I, 4 were grade II, and the remaining 2 were grade III. CT or MRI showed a well-defined (n = 8) or ill-defined (n = 3), oval (n = 4), irregular (n = 3), dumbbell-shaped (n = 3), and striped (n = 1) mass with heterogeneous (n = 10) or homogeneous (n = 1) density. The lesions appeared isointense (n = 4) or hypointense (n = 5) on T1-weighted MRI and mildly hyperintense (n = 3) or hyperintense (n = 6) on T2-weighted MRI. Bone destruction was observed in 7 cases, including osteolytic (n = 6) and osteoblastic (n = 1) patterns. Calcification was observed in only 1 case. On enhanced CT/MRI, marked (n = 9), mild (n = 1) heterogeneous, and marked homogeneous (n = 1) enhancement were observed in this study.

Conclusions: Spinal SFT/HPC commonly appears as a well-defined solitary mass characterized by a black and white appearance that is marked with heterogeneous enhancement with or without bone destruction.
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http://dx.doi.org/10.1016/j.wneu.2017.05.016DOI Listing
August 2017
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