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Research

Dang Research

Hien Dang, PhD
J. Wallace Davis & Gail G. Davis Chair in Surgery

1025 Walnut Street
603 College Building
Philadelphia, PA 19107

Faculty Profile
Division of Surgical Research

Publications

Our most recent publications indexed in Scopus:

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Highlighted Publications

Barry AE, Baldeosingh R, Lamm R, et al (2020) Hepatic Stellate Cells and Hepatocarcinogenesis. Front. Cell Dev. Biol., 8(709). 

Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create challenges in generating effective therapies.

Current studies reveal potential mechanisms through which activated HSCs drive hepatocarcinogenesis utilizing matricellular proteins and paracrine crosstalk within the TME. Since activated HSCs are primary secretors of ECM proteins during liver injury and inflammation, they help promote fibrogenesis, infiltrate the HCC stroma, and contribute to HCC development. In this review, we examine several recent studies revealing the roles of HSCs and their clinical implications in the development of fibrosis and cirrhosis within the hepatic TME.

Zhang K, Pomyen Y, Barry AE, et al. AGO2 Mediates MYC mRNA Stability in Hepatocellular Carcinoma [published online ahead of print, 2020 Jan 15]. Mol Cancer 

We are interested in utilizing several areas of RNA biology, translational, bioinformatics, and molecular biology to identify key oncogenic RBPs involved in transcriptomic alterations associated with disease states. For example, we have recently identified Argonaute 2 (AGO2) as an oncogenic RBP that can regulate the MYC transcript in a RISC-independent manner to promote HCC. By utilizing transcriptomics, we show that activated AGO2 preferentially affects MYC mRNAs by enhancing their stability. We’re now elucidating how AGO2 promotes HCC progression by directly interacting with many mRNA targets independent of miRNAs.

Dang, H et al (2017) Oncogenic Activation of the RNA Binding Protein NELFE and MYC Signaling in Hepatocellular Carcinoma. Cancer Cell, 32, 101-114.

Tumor initiation and maintenance require the selection of a unique tumor-promoting transcriptome induced by driver genes. Our study indicates that RNA binding proteins can mediate cancer-associated transcriptomic changes in hepatocellular carcinoma (HCC). Our work is consistent with the hypotheses that NELFE activation drives hepatocarcinogenesis and that the NELFE-MYC axis may be exploited as a viable therapeutic target for HCC.

Chaisaingmongkol, J et al (2017) Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma. Cancer Cell, 32, 57-70

Primary liver cancers have a complex mutational landscape with vast inter-tumor heterogeneity, which poses a major challenge to define actionable drivers. Here, we demonstrate that common molecular subtypes with key drivers are shared among Asian ICC andHCC patients through systematic integration of the genome, transcriptome, and metabolome. Our results indicate thatICC and HCC, while clinically treated as separate entities, share common molecular determinants, suggesting that a unifiedmolecular landscape of liver cancer is required to improve diagnosis and therapy.

Dang, H et al (2019) NELFE-Dependent MYC Signature Identifes a Unique Cancer Subtype in Hepatocellular Carcinoma. Scientific Reports, 9:3369.

We identified a gene signature to predict a unique subtype of HCC, which is associated with a poor prognosis in three independent cohorts encompassing diverse etiologies, demographics, and viral status. The application of our genes signature offers patients access to personalized risk assessments, which may be utilized to direct future care.

2021

Evaluating Outcomes Related to Donor and Recipient Metabolic Environment: Macrosteatotic Allografts and Nonalcoholic Steatohepatitis.

Altshuler PJ, Dang H, Frank AM, Shah AP, Glorioso J, Zhan T, Rios Diaz A, Shaheen O, Ramirez CB, Maley WR, Bodzin AS. Liver Transpl. 2021 Sep 26;. doi: 10.1002/lt.26313. [Epub ahead of print] PubMed PMID: 34564931.

Tumor metabolism and associated serum metabolites define prognostic subtypes of Asian hepatocellular carcinoma.

Pomyen Y, Budhu A, Chaisaingmongkol J, Forgues M, Dang H, Ruchirawat M, Mahidol C, Wang XW. Sci Rep. 2021 Jun 8;11(1):12097. doi: 10.1038/s41598-021-91560-1. PubMed PMID: 34103600; PubMed Central PMCID: PMC8187378.

Simultaneous liver kidney allocation policy and the Safety ​Net: an early examination of utilization and outcomes in the United States.

Altshuler PJ, Shah AP, Frank AM, Glorioso J, Dang H, Shaheen O, Patel K, Ramirez CB, Maley WR, Bodzin AS. Transpl Int. 2021 Apr 21;. doi: 10.1111/tri.13891. [Epub ahead of print] PubMed PMID: 33884677.

Intratumoral γδ T-Cell Infiltrates, Chemokine (C-C Motif) Ligand 4/Chemokine (C-C Motif) Ligand 5 Protein Expression and Survival in Patients With Hepatocellular Carcinoma.

Zhao N, Dang H, Ma L, Martin SP, Forgues M, Ylaya K, Hewitt SM, Wang XW. Hepatology. 2021 Mar;73(3):1045-1060. doi: 10.1002/hep.31412. PubMed PMID: 32502310.

2020

Serum IL6 as a Prognostic Biomarker and IL6R as a Therapeutic Target in Biliary Tract Cancers. Clin Cancer Res.

Høgdall D, O'Rourke CJ, Dehlendorff C, Larsen OF, Jensen LH, Johansen AZ, Dang H, Factor VM, Grunnet M, Mau-Sørensen M, Oliveira DVNP, Linnemann D, Boisen MK, Wang XW, Johansen JS, Andersen JB. 2020 Nov 1;26(21):5655-5667. doi: 10.1158/1078-0432.CCR-19-2700. Epub 2020 Sep 15. PubMed PMID: 32933994.

Hepatocellular Carcinoma-The Influence of Immunoanatomy and the Role of Immunotherapy.

Patel K, Lamm R, Altshuler P, Dang H, Shah AP. Int J Mol Sci. 2020 Sep 15;21(18). doi: 10.3390/ijms21186757. Review. PubMed PMID: 32942580; PubMed Central PMCID: PMC7555667.

Hepatic Stellate Cells and Hepatocarcinogenesis.

Barry AE, Baldeosingh R, Lamm R, Patel K, Zhang K, Dominguez DA, Kirton KJ, Shah AP, Dang H. Front Cell Dev Biol. 2020;8:709. doi: 10.3389/fcell.2020.00709. eCollection 2020. Review. PubMed PMID: 32850829; PubMed Central PMCID: PMC7419619.

PKM2 inhibition may reverse therapeutic resistance to transarterial chemoembolization in hepatocellular carcinoma.

Martin SP, Fako V, Dang H, Dominguez DA, Khatib S, Ma L, Wang H, Zheng W, Wang XW. J Exp Clin Cancer Res. 2020 Jun 3;39(1):99. doi: 10.1186/s13046-020-01605-y. PubMed PMID: 32487192; PubMed Central PMCID: PMC7268641.

AGO2 Mediates MYC mRNA Stability in Hepatocellular Carcinoma.

Zhang K, Pomyen Y, Barry AE, Martin SP, Khatib S, Knight L, Forgues M, Dominguez DA, Parhar R, Shah AP, Bodzin AS, Wang XW, Dang H. Mol Cancer Res. 2020 Apr;18(4):612-622. doi: 10.1158/1541-7786.MCR-19-0805. Epub 2020 Jan 15. PubMed PMID: 31941754; PubMed Central PMCID: PMC7127970.

Understanding the Cause and Consequence of Tumor Heterogeneity.

Khatib S, Pomyen Y, Dang H, Wang XW. Trends Cancer. 2020 Apr;6(4):267-271. doi: 10.1016/j.trecan.2020.01.010. Epub 2020 Feb 13. PubMed PMID: 32209440.

Depletion of TRRAP Induces p53-Independent Senescence in Liver Cancer by Down-Regulating Mitotic Genes.

Kwan SY, Sheel A, Song CQ, Zhang XO, Jiang T, Dang H, Cao Y, Ozata DM, Mou H, Yin H, Weng Z, Wang XW, Xue W. Hepatology. 2020 Jan;71(1):275-290. doi: 10.1002/hep.30807. Epub 2019 Aug 11. PubMed PMID: 31188495; PubMed Central PMCID: PMC6906267.

2019

Functional Genomic Complexity Defines Intratumor Heterogeneity and Tumor Aggressiveness in Liver Cancer.

Kwon SM, Budhu A, Woo HG, Chaisaingmongkol J, Dang H, Forgues M, Harris CC, Zhang G, Auslander N, Ruppin E, Mahidol C, Ruchirawat M, Wang XW. Sci Rep. 2019 Nov 15;9(1):16930. doi: 10.1038/s41598-019-52578-8. PubMed PMID: 31729408; PubMed Central PMCID: PMC6858353.

Genome-Wide RNAi Screen Identifies PMPCB as a Therapeutic Vulnerability in EpCAM+ Hepatocellular Carcinoma.

Takai A, Dang H, Oishi N, Khatib S, Martin SP, Dominguez DA, Luo J, Bagni R, Wu X, Powell K, Ye QH, Jia HL, Qin LX, Chen J, Mitchell GA, Luo X, Thorgeirsson SS, Wang XW. Cancer Res. 2019 May 1;79(9):2379-2391. doi: 10.1158/0008-5472.CAN-18-3015. Epub 2019 Mar 12. PubMed PMID: 30862714; PubMed Central PMCID: PMC6497533.

NELFE-Dependent MYC Signature Identifies a Unique Cancer Subtype in Hepatocellular Carcinoma.

Dang H, Pomyen Y, Martin SP, Dominguez DA, Yim SY, Lee JS, Budhu A, Shah AP, Bodzin AS, Wang XW. Sci Rep. 2019 Mar 4;9(1):3369. doi: 10.1038/s41598-019-39727-9. PubMed PMID: 30833661; PubMed Central PMCID: PMC6399236.

2018

Non-proteolytic ubiquitin modification of PPARγ by Smurf1 protects the liver from steatosis.

Zhu K, Tang Y, Xu X, Dang H, Tang LY, Wang X, Wang XW, Zhang YE. PLoS Biol. 2018 Dec;16(12):e3000091. doi: 10.1371/journal.pbio.3000091. eCollection 2018 Dec. PubMed PMID: 30566427; PubMed Central PMCID: PMC6317813.

Necroptosis microenvironment directs lineage commitment in liver cancer.

Seehawer M, Heinzmann F, D'Artista L, Harbig J, Roux PF, Hoenicke L, Dang H, Klotz S, Robinson L, Doré G, Rozenblum N, Kang TW, Chawla R, Buch T, Vucur M, Roth M, Zuber J, Luedde T, Sipos B, Longerich T, Heikenwälder M, Wang XW, Bischof O, Zender L. Nature. 2018 Oct;562(7725):69-75. doi: 10.1038/s41586-018-0519-y. Epub 2018 Sep 12. PubMed PMID: 30209397; PubMed Central PMCID: PMC8111790.

Single-cell analysis reveals cancer stem cell heterogeneity in hepatocellular carcinoma.

Zheng H, Pomyen Y, Hernandez MO, Li C, Livak F, Tang W, Dang H, Greten TF, Davis JL, Zhao Y, Mehta M, Levin Y, Shetty J, Tran B, Budhu A, Wang XW. Hepatology. 2018 Jul;68(1):127-140. doi: 10.1002/hep.29778. Epub 2018 May 9. PubMed PMID: 29315726; PubMed Central PMCID: PMC6033650.

The significance of intertumor and intratumor heterogeneity in liver cancer.

Liu J, Dang H, Wang XW. Exp Mol Med. 2018 Jan 5;50(1):e416. doi: 10.1038/emm.2017.165. Review. PubMed PMID: 29303512; PubMed Central PMCID: PMC5992990.

2017

Ubiquitin-specific protease 21 stabilizes BRCA2 to control DNA repair and tumor growth.

Liu J, Kruswick A, Dang H, Tran AD, Kwon SM, Wang XW, Oberdoerffer P. Nat Commun. 2017 Jul 26;8(1):137. doi: 10.1038/s41467-017-00206-2. PubMed PMID: 28743957; PubMed Central PMCID: PMC5526993.

Oncogenic Activation of the RNA Binding Protein NELFE and MYC Signaling in Hepatocellular Carcinoma.

Dang H, Takai A, Forgues M, Pomyen Y, Mou H, Xue W, Ray D, Ha KCH, Morris QD, Hughes TR, Wang XW. Cancer Cell. 2017 Jul 10;32(1):101-114.e8. doi: 10.1016/j.ccell.2017.06.002. PubMed PMID: 28697339; PubMed Central PMCID: PMC5539779.

Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma.

Chaisaingmongkol J, Budhu A, Dang H, Rabibhadana S, Pupacdi B, Kwon SM, Forgues M, Pomyen Y, Bhudhisawasdi V, Lertprasertsuke N, Chotirosniramit A, Pairojkul C, Auewarakul CU, Sricharunrat T, Phornphutkul K, Sangrajrang S, Cam M, He P, Hewitt SM, Ylaya K, Wu X, Andersen JB, Thorgeirsson SS, Waterfall JJ, Zhu YJ, Walling J, Stevenson HS, Edelman D, Meltzer PS, Loffredo CA, Hama N, Shibata T, Wiltrout RH, Harris CC, Mahidol C, Ruchirawat M, Wang XW. Cancer Cell. 2017 Jul 10;32(1):57-70.e3. doi: 10.1016/j.ccell.2017.05.009. Epub 2017 Jun 22. PubMed PMID: 28648284; PubMed Central PMCID: PMC5524207.

Cancer exosomes: wanted by many, explored by few, waiting for one.

Dang H, Zhao X, Chow CW. Ann Transl Med. 2017 May;5(10):220. doi: 10.21037/atm.2017.02.21. PubMed PMID: 28603735; PubMed Central PMCID: PMC5451620.

2016

LTβR signalling preferentially accelerates oncogenic AKT-initiated liver tumours.

Scarzello AJ, Jiang Q, Back T, Dang H, Hodge D, Hanson C, Subleski J, Weiss JM, Stauffer JK, Chaisaingmongkol J, Rabibhadana S, Ruchirawat M, Ortaldo J, Wang XW, Norris PS, Ware CF, Wiltrout RH. Gut. 2016 Oct;65(10):1765-75. doi: 10.1136/gutjnl-2014-308810. Epub 2015 Jul 23. PubMed PMID: 26206664; PubMed Central PMCID: PMC5036232.

Three-dimensional Organotypic Culture Models of Human Hepatocellular Carcinoma.

Takai A, Fako V, Dang H, Forgues M, Yu Z, Budhu A, Wang XW. Sci Rep. 2016 Feb 16;6:21174. doi: 10.1038/srep21174. PubMed PMID: 26880118; PubMed Central PMCID: PMC4754778.

2015

Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma.

Ji J, Eggert T, Budhu A, Forgues M, Takai A, Dang H, Ye Q, Lee JS, Kim JH, Greten TF, Wang XW. Hepatology. 2015 Aug;62(2):481-95. doi: 10.1002/hep.27822. Epub 2015 Apr 28. PubMed PMID: 25833323; PubMed Central PMCID: PMC4515211.

The EGFR/ErbB3 Pathway Acts as a Compensatory Survival Mechanism upon c-Met Inhibition in Human c-Met+ Hepatocellular Carcinoma.

Steinway SN, Dang H, You H, Rountree CB, Ding W. PLoS One. 2015;10(5):e0128159. doi: 10.1371/journal.pone.0128159. eCollection 2015. PubMed PMID: 26000702; PubMed Central PMCID: PMC4441360.

Induction of tumor initiation is dependent on CD44s in c-Met⁺ hepatocellular carcinoma.

Dang H, Steinway SN, Ding W, Rountree CB. BMC Cancer. 2015 Mar 21;15:161. doi: 10.1186/s12885-015-1166-4. PubMed PMID: 25886575; PubMed Central PMCID: PMC4380258.

2014

Identification of drivers from cancer genome diversity in hepatocellular carcinoma.

Takai A, Dang HT, Wang XW. Int J Mol Sci. 2014 Jun 20;15(6):11142-60. doi: 10.3390/ijms150611142. Review. PubMed PMID: 24955791; PubMed Central PMCID: PMC4100204.

The origin of cancer stem cells.

Dang HT, Budhu A, Wang XW. J Hepatol. 2014 Jun;60(6):1304-5. doi: 10.1016/j.jhep.2014.03.001. Epub 2014 Mar 13. PubMed PMID: 24631602.

2012

miR-200b restoration and DNA methyltransferase inhibitor block lung metastasis of mesenchymal-phenotype hepatocellular carcinoma.

Ding W, Dang H, You H, Steinway S, Takahashi Y, Wang HG, Liao J, Stiles B, Albert R, Rountree CB. Oncogenesis. 2012 Jun 11;1:e15. doi: 10.1038/oncsis.2012.15. PubMed PMID: 23552699; PubMed Central PMCID: PMC3412647.

2011

Isolation of CD133+ liver stem cells for clonal expansion.

Rountree CB, Ding W, Dang H, Vankirk C, Crooks GM. J Vis Exp. 2011 Oct 10;(56). doi: 10.3791/3183. PubMed PMID: 22006186; PubMed Central PMCID: PMC3227180.

Snail1 induces epithelial-to-mesenchymal transition and tumor initiating stem cell characteristics.

Dang H, Ding W, Emerson D, Rountree CB. BMC Cancer. 2011 Sep 19;11:396. doi: 10.1186/1471-2407-11-396. PubMed PMID: 21929801; PubMed Central PMCID: PMC3189192.

c-Met represents a potential therapeutic target for personalized treatment in hepatocellular carcinoma.

You H, Ding W, Dang H, Jiang Y, Rountree CB. Hepatology. 2011 Sep 2;54(3):879-89. doi: 10.1002/hep.24450. Epub 2011 Jul 19. PubMed PMID: 21618573; PubMed Central PMCID: PMC3181384.

2010

Expansion of hepatic tumor progenitor cells in Pten-null mice requires liver injury and is reversed by loss of AKT2.

Galicia VA, He L, Dang H, Kanel G, Vendryes C, French BA, Zeng N, Bayan JA, Ding W, Wang KS, French S, Birnbaum MJ, Rountree CB, Stiles BL. Gastroenterology. 2010 Dec;139(6):2170-82. doi: 10.1053/j.gastro.2010.09.002. Epub 2010 Sep 15. PubMed PMID: 20837017; PubMed Central PMCID: PMC2997180.

Clinical application for the preservation of phospho-proteins through in-situ tissue stabilization.

Rountree CB, Van Kirk CA, You H, Ding W, Dang H, VanGuilder HD, Freeman WM. Proteome Sci. 2010 Nov 22;8:61. doi: 10.1186/1477-5956-8-61. PubMed PMID: 21092202; PubMed Central PMCID: PMC3000382.

Epithelial-to-mesenchymal transition of murine liver tumor cells promotes invasion.

Ding W, You H, Dang H, LeBlanc F, Galicia V, Lu SC, Stiles B, Rountree CB. Hepatology. 2010 Sep;52(3):945-53. doi: 10.1002/hep.23748. PubMed PMID: 20564331; PubMed Central PMCID: PMC3032356.

2008

SALL4 is a key regulator of survival and apoptosis in human leukemic cells.

Yang J, Chai L, Gao C, Fowles TC, Alipio Z, Dang H, Xu D, Fink LM, Ward DC, Ma Y. Blood. 2008 Aug 1;112(3):805-13. doi: 10.1182/blood-2007-11-126326. Epub 2008 May 16. PubMed PMID: 18487508; PubMed Central PMCID: PMC2481537.

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