Research Summary

Research in our laboratory focuses on the regulation of the pathways by which salts, sugars, peptides and proteins cross epithelial barriers; and how this changes early in the process of cancer. We are particularly interested in the regulation of the tight junction, which limits transit across the epithelium through the paracellular or "between cell" pathway. Phorbol esters, which are known tumor promoters, activate PKC in our renal and gastrointestinal epithelial cell culture models and increase tight junctional permeability [1 & 2]. We have recently shown through study of the localization and down regulation of various PKC isoforms that changes in tight junction permeability correlate with phorbol ester-induced changes in the PKC isoform, PKC-alpha [3] and that specific tight junction proteins, such as occludin and claudins, may be targeted [4]. The leak of tight junctions in cancerous epithelial tissues may allow growth factors like EGF to enter tumor microenvironments [10].

Parallel studies from our group have demonstrated that the tight junctions between epithelia of normal human colon mucosa act as good barriers whereas the junctions between the epithelia of adenocarcinomas are all "leaky" [5]. Such leakiness may associate with aberrant colon crypts as well.  The tight junction proteins of metaplastic epithelium of Barrett's esophagus also have a leaky character [6].  In separate studies focused on inflammation, we have shown that the proinflammatory cytokine, TNF, can induce a transient and minor increase in tight junctional permeability that associates with the induction of limited apoptotic cell death and rapid remodeling of the surviving epithelial cells about the dying cell. This prevents a sustained and major increase in permeability [7 & 8].

Inflammatory bowel disease associated with increased colon cancer risk has been linked with increased tight junction permeability as well as increased levels of proinflammatory cytokines, among them TNF. The biological significance of these findings is that if tight junctions become "leaky" in the course of tumor promotion or inflammation, growth factors normally restricted to the GI Lumen may cross the epithelial barrier, access their receptors and stimulate cell growth and motility [9 & 10].

Future work will focus both on molecular mechanisms of tight junction regulation as well as clinical studies exploring its disease implications, particularly in esophageal, stomach and colon cancer. A major multi center clinical study in the detection and progression of esophageal and stomach cancer is currently underway.

Clinical Trials

Selected Publications

1. Mullin JM.  2004.  Epithelial barriers, compartmentation and cancer.  Science STK Jan 13; 2004(216): pe2.
2. Rendon-Huerta E, Valenzano MC, Mullin JM, Trembeth SE, Kothari R, Hameed B, Mercogliano G, Thornton JJ.  2003.  Comparison of three integral tight junction barrier proteins in Barrett's epithelium versus normal esophageal epithelium.  Am J Gastroenterol. 98:1901-1903.
3. Marano CW, Garulacan LA, Ginanni N, Mullin JM.  2001.  Phorbol ester treatment increases paracellular permeability across IEC-18.  Dig Dis Sci. 46:1490-1499.
4. Clarke, H., Peralta Soler, A., Mullin, J.M. 2000. Protein Kinase C Activation Leads to Dephosphorylation of Occludin and Tight Junction Permeability Increase in LLC-PK1 Epithelial Cell Sheets. J. Cell Sci. 113:3187-3196.
5. Peralta Soler, A., Miller, R.D, Laughlin, K.V., Carp, N.Z., Klurfeld, D.M. and Mullin, J.M. 1999. Increased Tight Junctional Permeability is Associated with the Development of Colon Cancer. Carcinogenesis 20:1425-1431.
6. Mullin, J.M., Ginanni, N., Laughlin, K.V. 1998. Protein kinase C activation increases transepithelial transport of biologically active insulin. Cancer Research 58:1641-1645.
7. Mullin, J.M., Kampherstein, J.A., Laughlin, K.V., Saladik, D.T., Peralta Soler, A. 1997. Transepithelial paracellular leakiness induced by chronic phorbol ester exposure correlates with polyp-like foci and redistribution of protein kinase C-alpha. Carcinogenseis 18:2339-2345.
8. Peralta Soler, A., Mullin, J.M., Knudsen, K.A., Marano, C.W. 1996. Tissue remodeling during tumor necrosis factor-induced apoptosis in LLC-PK1 renal epithelial cells. Am. J. Physiology 270:F869-F879.
9. Mullin, J.M., Laughlin, K.V., Marano, C.W., Russo, L.M., Peralta Soler, A. 1992. Modulation of tumor necrosis factor-induced increase in renal (LLC-PK1) transepithelial permeability. Am. J. Physiology 263:F915-F924.
10. Mullin, J.M., O’Brien, T.G. 1986. Effect of tumor promoters on LLC-PK1 renal epithelial tight junctions and transepithelial fluxes. Am. J. Physiology 251:C597-C602

Personnel

• Mary Carmen Valenzano, Research Technician II
• Lisa Murray , Graduate Student
• Vishal Jain, MD, GI Fellow
• Kevin Wolov, DO, GI Fellow
• Anagha Deshmukh, MD, GI Fellow
• Paul Allegretti, DO, Medical Resident
• Jon Verrechio, DO, Medical Resident
• David Schmitt, MD, Medical Resident

PDF Posters

• Esomeprazole Induces a Transepithelial Gastroesophageal Mucosal Leak in GERD Patients and Healthy Controls
• Absence of Na+/Sugar Cotransport Activity in Barrett’s Metaplasia