Profile

Wael El-Rifai, MD., Ph.D.
H. Williams Scott Jr. Chair in Surgery
Director, Surgical Oncology Research
Professor, Surgery & Cancer Biology


Dr. El-Rifai has a long-standing interest in understanding the modulation of molecular pathways through genetic and epigenetic events. His research is focused on upper gastrointestinal carcinomas (UGCs) with two main goals:

1. Translational OncoGenomics in upper gastrointestinal carcinomas
The El-Rifai laboratory has extensive expertise in the dissection of genetic and epigenetic alterations in upper gastrointestinal carcinomas (UGC). This group of tumors includes distal gastric tumors and proximal adenocarcinomas of the gastroesophageal junctional (GEJ) and lower esophagus. Proximal adenocarcinomas are the fastest rising tumors in the United States as well as in the rest of the western world. In my laboratory, we apply comprehensive, molecular-analysis-approaches with the integration of data in order to understand the molecular anatomy of these tumors. Several high-throughput technologies are utilized in his research. These include comparative genomic hybridization, microarrays, serial analysis of gene expression, and proteomic approaches. The El-Rifai laboratory identified a number of genomic hot spots and has systematically characterized the 1q, 17q, and 20q amplicons by combining the genomic data with gene expression data. At 17q21 he identified and characterized a 168 kb critical amplicon region that contains several known oncogenes side-by-side such as ERBB2, GRB7, and TOP2A. We have collected more than 400 tumors on tissue microarrays. These TMAs are continuously analyzed for identification of the clinical and histopathological significance of molecular alterations. Dr. El-Rifai’s lab was the first group of investigators to reveal Darpp-32 and its isoforms as novel cancer genes.
Our research extends to encompass animal models as tools of identification of tumor development and progression. In this direction, we have obtained TFF1 knockout mice that develop premalignant gastric dysplasia. Dr. El-Rifai laboratory has characterized this model and used it to identify alterations in molecular pathways that occur in a premalignant state. Using this approach, his research group discovered a number of previously unknown genes in gastric tumorigenesis and was able to validate the findings in human premalignant conditions. These genes include GPx3, Claudin-7, and Caveolin.
Dr. El-Rifai has demonstrated DNA promoter hypermethylation as a mechanism of down-regulation and loss of expression of several novel genes such as MT3, MGMT, DAPK, and GPX3. He has further shown that some of these changes are early events initiated in premalignant states such as in Barrett’s dysplasia. Recently, we have added to our laboratory the cutting-edge, pyrosequencing technology (Biotage) for a high through-put, robust, quantitative analysis of promoter CpG methylation sites.

2. Cellular effects and signaling transduction in UGCs
In line with his translational research component, Dr. El-Rifai laboratory is primarily interested in identifying anti-apoptotic/pro-survival targets that contribute to drug resistance. At this time, the work is focused in understanding the p53-dependent and independent mechanisms that contribute to this phenotype. Our work has demonstrated that Darpp-32 is a potent antiapoptotic gene that provides a phenotype that is drug resistant to cancer cells against several chemotherapeutic agents. This drug resistant phenotype was through a p53-independent mechanism that included up-regulation and activation of mitochondrial Bcl2 prosurvival proteins. In my laboratory, we use normal and transformed cells, specific antibodies and purified protein kinases to show phosphorylation controls activity. We continue to establish the oncogenic properties and downstream targets of Darpp-32 and/or t-Darpp in order to understand the signaling pathways that are regulated by Darpp-32 in cancer. In addition to studies on Dar

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. APE1-mediated DNA damage repair provides survival advantage for esophageal adenocarcinoma cells in response to acidic bile salts. Hong J, Chen Z, Peng D, Zaika A, Revetta F, Washington MK, Belkhiri A, El-Rifai W (2016) Oncotarget 7(13): 16688-702
    › Primary publication · 26934647 (PubMed) · PMC4941344 (PubMed Central)
  2. DARPP-32: from neurotransmission to cancer. Belkhiri A, Zhu S, El-Rifai W (2016) Oncotarget 7(14): 17631-40
    › Primary publication · 26872373 (PubMed) · PMC4951238 (PubMed Central)
  3. Activin a signaling regulates cell invasion and proliferation in esophageal adenocarcinoma. Taylor C, Loomans HA, Le Bras GF, Koumangoye RB, Romero-Morales AI, Quast LL, Zaika AI, El-Rifai W, Andl T, Andl CD (2015) Oncotarget 6(33): 34228-44
    › Primary publication · 26447543 (PubMed) · PMC4741448 (PubMed Central)
  4. Trefoil factor 1 expression suppresses Helicobacter pylori-induced inflammation in gastric carcinogenesis. Soutto M, Chen Z, Katsha AM, Romero-Gallo J, Krishna US, Piazuelo MB, Washington MK, Peek RM, Belkhiri A, El-Rifai WM (2015) Cancer 121(24): 4348-58
    › Primary publication · 26372254 (PubMed) · PMC4670586 (PubMed Central)
  5. DNA Methylation Predicts Progression of Human Gastric Lesions. Schneider BG, Mera R, Piazuelo MB, Bravo JC, Zabaleta J, Delgado AG, Bravo LE, Wilson KT, El-Rifai W, Peek RM, Correa P (2015) Cancer Epidemiol Biomarkers Prev 24(10): 1607-13
    › Primary publication · 26269563 (PubMed) · PMC4592454 (PubMed Central)
  6. Regulation of CD44E by DARPP-32-dependent activation of SRp20 splicing factor in gastric tumorigenesis. Zhu S, Chen Z, Katsha A, Hong J, Belkhiri A, El-Rifai W (2016) Oncogene 35(14): 1847-56
    › Primary publication · 26119931 (PubMed) · PMC4486340 (PubMed Central)
  7. Aurora kinase A in gastrointestinal cancers: time to target. Katsha A, Belkhiri A, Goff L, El-Rifai W (2015) Mol Cancer : 106
    › Primary publication · 25987188 (PubMed) · PMC4436812 (PubMed Central)
  8. Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis. Soutto M, Romero-Gallo J, Krishna U, Piazuelo MB, Washington MK, Belkhiri A, Peek RM, El-Rifai W (2015) Oncotarget 6(20): 17911-22
    › Primary publication · 25980439 (PubMed) · PMC4627225 (PubMed Central)
  9. Gastric tumour-derived ANGPT2 regulation by DARPP-32 promotes angiogenesis. Chen Z, Zhu S, Hong J, Soutto M, Peng D, Belkhiri A, Xu Z, El-Rifai W (2016) Gut 65(6): 925-34
    › Primary publication · 25779598 (PubMed) · PMC4573388 (PubMed Central)
  10. Helicobacter pylori bacteria alter the p53 stress response via ERK-HDM2 pathway. Bhardwaj V, Noto JM, Wei J, Andl C, El-Rifai W, Peek RM, Zaika AI (2015) Oncotarget 6(3): 1531-43
    › Primary publication · 25605238 (PubMed) · PMC4359312 (PubMed Central)
  11. Advances in targeted therapies and new promising targets in esophageal cancer. Belkhiri A, El-Rifai W (2015) Oncotarget 6(3): 1348-58
    › Primary publication · 25593196 (PubMed) · PMC4359299 (PubMed Central)
  12. Translational research on Barrett's esophagus. Baruah A, Buttar N, Chandra R, Chen X, Clemons NJ, Compare D, El-Rifai W, Gu J, Houchen CW, Koh SY, Li W, Nardone G, Phillips WA, Sharma A, Singh I, Upton MP, Vega KJ, Wu X (2014) Ann N Y Acad Sci : 170-86
    › Primary publication · 25266024 (PubMed)
  13. Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis. Soutto M, Peng D, Katsha A, Chen Z, Piazuelo MB, Washington MK, Belkhiri A, Correa P, El-Rifai W (2015) Gut 64(7): 1028-39
    › Primary publication · 25107557 (PubMed) · PMC4320984 (PubMed Central)
  14. Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner. Wei J, Noto JM, Zaika E, Romero-Gallo J, Piazuelo MB, Schneider B, El-Rifai W, Correa P, Peek RM, Zaika AI (2015) Gut 64(7): 1040-8
    › Primary publication · 25080447 (PubMed) · PMC4312278 (PubMed Central)
  15. TFF1 activates p53 through down-regulation of miR-504 in gastric cancer. Soutto M, Chen Z, Saleh MA, Katsha A, Zhu S, Zaika A, Belkhiri A, El-Rifai W (2014) Oncotarget 5(14): 5663-73
    › Primary publication · 25015107 (PubMed) · PMC4170596 (PubMed Central)
  16. Glutathione Peroxidase 7 Suppresses Bile Salt-Induced Expression of Pro-Inflammatory Cytokines in Barrett's Carcinogenesis. Peng DF, Hu TL, Soutto M, Belkhiri A, El-Rifai W (2014) J Cancer 5(7): 510-7
    › Primary publication · 24963355 (PubMed) · PMC4067510 (PubMed Central)
  17. AURKA regulates JAK2-STAT3 activity in human gastric and esophageal cancers. Katsha A, Arras J, Soutto M, Belkhiri A, El-Rifai W (2014) Mol Oncol 8(8): 1419-28
    › Primary publication · 24953013 (PubMed) · PMC4254172 (PubMed Central)
  18. Promoter hypermethylation and suppression of glutathione peroxidase 3 are associated with inflammatory breast carcinogenesis. Mohamed MM, Sabet S, Peng DF, Nouh MA, El-Shinawi M, El-Rifai W (2014) Oxid Med Cell Longev : 787195
    › Primary publication · 24790704 (PubMed) · PMC3980917 (PubMed Central)
  19. Loss of glutathione peroxidase 7 promotes TNF-α-induced NF-κB activation in Barrett's carcinogenesis. Peng DF, Hu TL, Soutto M, Belkhiri A, El-Rifai W (2014) Carcinogenesis 35(7): 1620-8
    › Primary publication · 24692067 (PubMed) · PMC4076814 (PubMed Central)
  20. Antitumor activity of cell-permeable p18(INK4c) with enhanced membrane and tissue penetration. Lim J, Kim J, Duong T, Lee G, Kim J, Yoon J, Kim J, Kim H, Ruley HE, El-Rifai W, Jo D (2012) Mol Ther 20(8): 1540-9
    › Primary publication · 22617107 (PubMed) · PMC3412482 (PubMed Central)
  21. Resistance to TRAIL is mediated by DARPP-32 in gastric cancer. Belkhiri A, Zhu S, Chen Z, Soutto M, El-Rifai W (2012) Clin Cancer Res 18(14): 3889-900
    › Primary publication · 22589394 (PubMed) · PMC3399047 (PubMed Central)
  22. The aurora kinase A inhibitor MLN8237 enhances cisplatin-induced cell death in esophageal adenocarcinoma cells. Sehdev V, Peng D, Soutto M, Washington MK, Revetta F, Ecsedy J, Zaika A, Rau TT, Schneider-Stock R, Belkhiri A, El-Rifai W (2012) Mol Cancer Ther 11(3): 763-74
    › Primary publication · 22302096 (PubMed) · PMC3297687 (PubMed Central)
  23. Glutathione peroxidase 7 protects against oxidative DNA damage in oesophageal cells. Peng D, Belkhiri A, Hu T, Chaturvedi R, Asim M, Wilson KT, Zaika A, El-Rifai W (2012) Gut 61(9): 1250-60
    › Primary publication · 22157330 (PubMed) · PMC3419307 (PubMed Central)
  24. Cell-permeable NM23 blocks the maintenance and progression of established pulmonary metastasis. Lim J, Jang G, Kang S, Lee G, Nga do TT, Phuong do TL, Kim H, El-Rifai W, Ruley HE, Jo D (2011) Cancer Res 71(23): 7216-25
    › Primary publication · 21987726 (PubMed)
  25. BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinoma. Williams CS, Zhang B, Smith JJ, Jayagopal A, Barrett CW, Pino C, Russ P, Presley SH, Peng D, Rosenblatt DO, Haselton FR, Yang JL, Washington MK, Chen X, Eschrich S, Yeatman TJ, El-Rifai W, Beauchamp RD, Chang MS (2011) J Clin Invest 121(10): 4056-69
    › Primary publication · 21911938 (PubMed) · PMC3195453 (PubMed Central)
  26. p73 protein regulates DNA damage repair. Zaika E, Wei J, Yin D, Andl C, Moll U, El-Rifai W, Zaika AI (2011) FASEB J 25(12): 4406-14
    › Primary publication · 21891782 (PubMed) · PMC3236618 (PubMed Central)
  27. Location-specific epigenetic regulation of the metallothionein 3 gene in esophageal adenocarcinomas. Peng D, Hu TL, Jiang A, Washington MK, Moskaluk CA, Schneider-Stock R, El-Rifai W (2011) PLoS One 6(7): e22009
    › Primary publication · 21818286 (PubMed) · PMC3139601 (PubMed Central)
  28. DARPP-32 increases interactions between epidermal growth factor receptor and ERBB3 to promote tumor resistance to gefitinib. Zhu S, Belkhiri A, El-Rifai W (2011) Gastroenterology 141(5): 1738-48.e1-2
    › Primary publication · 21741919 (PubMed) · PMC3202055 (PubMed Central)
  29. Loss of TFF1 is associated with activation of NF-κB-mediated inflammation and gastric neoplasia in mice and humans. Soutto M, Belkhiri A, Piazuelo MB, Schneider BG, Peng D, Jiang A, Washington MK, Kokoye Y, Crowe SE, Zaika A, Correa P, Peek RM, El-Rifai W (2011) J Clin Invest 121(5): 1753-67
    › Primary publication · 21490402 (PubMed) · PMC3083788 (PubMed Central)
  30. Reduction of 8-iso-prostaglandin F2α in the first week after Roux-en-Y gastric bypass surgery. Ueda Y, Hajri T, Peng D, Marks-Shulman PA, Tamboli RA, Shukrallah B, Saliba J, Jabbour K, El-Rifai W, Abumrad NA, Abumrad NN (2011) Obesity (Silver Spring) 19(8): 1663-8
    › Primary publication · 21475145 (PubMed) · PMC3176330 (PubMed Central)
  31. Regulation of β-catenin by t-DARPP in upper gastrointestinal cancer cells. Vangamudi B, Zhu S, Soutto M, Belkhiri A, El-Rifai W (2011) Mol Cancer : 32
    › Primary publication · 21447180 (PubMed) · PMC3075216 (PubMed Central)
  32. Genetic analysis using microarrays. El-Rifai W, Knuutila S (2001) Methods Mol Med : 195-203
    › Primary publication · 21318828 (PubMed)
  33. Comparative genomic hybridization technique. El-Rifai WE, Knuutila S (2001) Methods Mol Med : 25-33
    › Primary publication · 21318813 (PubMed)
  34. Epigenetic silencing of somatostatin in gastric cancer. Jackson K, Soutto M, Peng D, Hu T, Marshal D, El-Rifai W (2011) Dig Dis Sci 56(1): 125-30
    › Primary publication · 20927589 (PubMed) · PMC3082506 (PubMed Central)
  35. Characterization of ΔNp73 expression and regulation in gastric and esophageal tumors. Vilgelm AE, Hong SM, Washington MK, Wei J, Chen H, El-Rifai W, Zaika A (2010) Oncogene 29(43): 5861-8
    › Primary publication · 20676143 (PubMed) · PMC4152004 (PubMed Central)
  36. Dopamine and cAMP regulated phosphoprotein MW 32 kDa is overexpressed in early stages of gastric tumorigenesis. Mukherjee K, Peng D, Brifkani Z, Belkhiri A, Pera M, Koyama T, Koehler EA, Revetta FL, Washington MK, El-Rifai W (2010) Surgery 148(2): 354-63
    › Primary publication · 20580047 (PubMed) · PMC2919779 (PubMed Central)
  37. Epigenetic and genetic silencing of CHFR in esophageal adenocarcinomas. Soutto M, Peng D, Razvi M, Ruemmele P, Hartmann A, Roessner A, Schneider-Stock R, El-Rifai W (2010) Cancer 116(17): 4033-42
    › Primary publication · 20564104 (PubMed) · PMC2930066 (PubMed Central)
  38. Regulation of p53 tumor suppressor by Helicobacter pylori in gastric epithelial cells. Wei J, Nagy TA, Vilgelm A, Zaika E, Ogden SR, Romero-Gallo J, Piazuelo MB, Correa P, Washington MK, El-Rifai W, Peek RM, Zaika A (2010) Gastroenterology 139(4): 1333-43
    › Primary publication · 20547161 (PubMed) · PMC2949494 (PubMed Central)
  39. Esophageal adenocarcinoma: treatment modalities in the era of targeted therapy. Mukherjee K, Chakravarthy AB, Goff LW, El-Rifai W (2010) Dig Dis Sci 55(12): 3304-14
    › Primary publication · 20300841 (PubMed) · PMC2890301 (PubMed Central)
  40. Promoter DNA hypermethylation in gastric biopsies from subjects at high and low risk for gastric cancer. Schneider BG, Peng DF, Camargo MC, Piazuelo MB, Sicinschi LA, Mera R, Romero-Gallo J, Delgado AG, Bravo LE, Wilson KT, Peek RM, Correa P, El-Rifai W (2010) Int J Cancer 127(11): 2588-97
    › Primary publication · 20178103 (PubMed) · PMC2916942 (PubMed Central)
  41. Aurora kinase inhibitors--rising stars in cancer therapeutics? Dar AA, Goff LW, Majid S, Berlin J, El-Rifai W (2010) Mol Cancer Ther 9(2): 268-78
    › Primary publication · 20124450 (PubMed) · PMC2820587 (PubMed Central)
  42. Profiling bladder cancer organ site-specific metastasis identifies LAMC2 as a novel biomarker of hematogenous dissemination. Smith SC, Nicholson B, Nitz M, Frierson HF, Smolkin M, Hampton G, El-Rifai W, Theodorescu D (2009) Am J Pathol 174(2): 371-9
    › Primary publication · 19147813 (PubMed) · PMC2630547 (PubMed Central)
  43. Overexpression of OATP1B3 confers apoptotic resistance in colon cancer. Lee W, Belkhiri A, Lockhart AC, Merchant N, Glaeser H, Harris EI, Washington MK, Brunt EM, Zaika A, Kim RB, El-Rifai W (2008) Cancer Res 68(24): 10315-23
    › Primary publication · 19074900 (PubMed) · PMC2605661 (PubMed Central)
  44. The aurora kinase A regulates GSK-3beta in gastric cancer cells. Dar AA, Belkhiri A, El-Rifai W (2009) Oncogene 28(6): 866-75
    › Primary publication · 19060929 (PubMed) · PMC2642527 (PubMed Central)
  45. Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus. Kuester D, El-Rifai W, Peng D, Ruemmele P, Kroeckel I, Peters B, Moskaluk CA, Stolte M, Mönkemüller K, Meyer F, Schulz HU, Hartmann A, Roessner A, Schneider-Stock R (2009) Cancer Lett 275(1): 117-26
    › Primary publication · 19027227 (PubMed) · PMC4028828 (PubMed Central)
  46. Aurora kinase A inhibition leads to p73-dependent apoptosis in p53-deficient cancer cells. Dar AA, Belkhiri A, Ecsedy J, Zaika A, El-Rifai W (2008) Cancer Res 68(21): 8998-9004
    › Primary publication · 18974145 (PubMed) · PMC2587495 (PubMed Central)
  47. Therapeutic prospects for p73 and p63: rising from the shadow of p53. Vilgelm A, El-Rifai W, Zaika A (2008) Drug Resist Updat 11(4-5): 152-63
    › Primary publication · 18801697 (PubMed) · PMC2585826 (PubMed Central)
  48. Deregulation of MUC4 in gastric adenocarcinoma: potential pathobiological implication in poorly differentiated non-signet ring cell type gastric cancer. Senapati S, Chaturvedi P, Sharma P, Venkatraman G, Meza JL, El-Rifai W, Roy HK, Batra SK (2008) Br J Cancer 99(6): 949-56
    › Primary publication · 18781152 (PubMed) · PMC2538752 (PubMed Central)
  49. Expression of t-DARPP mediates trastuzumab resistance in breast cancer cells. Belkhiri A, Dar AA, Peng DF, Razvi MH, Rinehart C, Arteaga CL, El-Rifai W (2008) Clin Cancer Res 14(14): 4564-71
    › Primary publication · 18579663 (PubMed) · PMC2842884 (PubMed Central)