Yan-hua Chen, Ph.D.

Research

Our laboratory studies roles of tight junction proteins in epithelial cell functions and their involvement in human diseases such as hypertension, inflammation, and cancer. Tight junctions serve as a permeability barrier regulating the passage of ions and small molecules through the paracellular pathway (between cells). Tight junction plays a crucial role in maintaining tissue homeostasis by keeping the extracellular fluid within the physiological range. Disruption of tight junction integrity leads to a number of human diseases such as renal magnesium wasting. We use various approaches including targeted gene deletion, molecular and cell biology, and electrophysiology to study protein-protein interactions, paracellular permeability regulation, and the role of protein kinases in the regulation of tight junction formation and functions.

Using our claudin-7 knockout mouse model and cell culture system, we are currently working on the following projects: (1) Phosphorylation of tight junction proteins and the role of protein kinases in modulating paracellular ion permeability in kidneys. We are investigating the regulation of tight junction functions by WNK4 kinase, mutations of which cause hypertension in PHAII; (2) Claudin functions in intestines. Deletion of claudin-7 in mouse intestines leads to mucosal ulcerations, epithelial cell sloughing and intestinal inflammation. Our laboratory is investigating the underlying molecular mechanism causing these defects using microarrays, RT-PCR, biochemistry, and imaging technology; (3) Roles of claudin proteins in cancer. Our recent publications indicate that overexpression of claudin-7 reduces cell growth in human lung cancer cells, and that suppression of claudin-7 expression promotes human lung cancer cell proliferation and detachment. We are currently investigating how claudin-7 interactions with integrin signaling influences cancer cell growth, adhesion, and invasion.

Selected Publications

Xing, T.S., L.J. Benderman, S. Sabu, J. Parker, J. Yang, Q. Lu, L. Ding, and Y.-H. Chen. 2019. Tight junction protein claudin-7 is essential for intestinal epithelial stem cell self-renewal and differentiation. Cell Mol. Gastroenterol. Hepatol. In Press.

Aguilar, B.J., Y.X. Zhao, H.C. Zhou, S.Q. Huo, Y.-H. Chen, and Q. Lu. 2019. Inhibition of Cdc42-intersectin interaction by small molecule ZCL367 impedes cancer cell cycle progression, proliferation, migration, and tumor growth. Cancer Biol. and Ther. 20 (6): 740–749.

Kim, D.H., Q. Lu, and Y.-H. Chen. 2019. Claudin 7 modulates cell matrix adhesion that controls cell migration, invasion and attachment of human HCC827 lung cancer cells. Oncol. Lett. 17:2890-2896.

Fan. J., R. Tatum, J. Hoggard, and Y.-H. Chen. 2019. Claudin-7 modulates Cl- and Na+ homeostasis and WNK4 expression in renal collecting duct cells. Int. J. Mol. Sci. 20 (15): 3798.

Ravisankar, S., R. Tatum, P.M. Garg, M. Herco, P.S. Shekhawat, and Y.-H. Chen. 2018. Necrotizing enterocolitis leads to disruption of tight junctions and increase in gut permeability in a mouse model. BMC Pediatr. 18:372.

Kim, D.H., T.S. Xing, Z.B. Yang, R. Dudek, Q. Lu, and Y.-H. Chen. 2017. Epithelial mesenchymal transition in embryonic development, tissue repair and cancer: A comprehensive overview. J. Clin. Med. 7(1): 1-25.

Xing, T.S., R. Camacho Salazar, and Y.-H. Chen. 2017. Animal models for studying epithelial barriers in neonatal necrotizing enterocolitis, inflammatory bowel disease and colorectal cancer. Tissue Barriers. 5:4, e1356901.

Garg, P.M., R. Tatum, S. Ravisankar, P.S. Shekhawat, and Y.-H. Chen. 2015. Necrotizing enterocolitis in a mouse model leads to widespread renal inflammation, acute kidney injury, and disruption of renal tight junction proteins. Pediatr. Res. 146:1-6.

Lu, Z., D.H. Kim, J.M. Fan, Q. Lu, K. Verbanac, L. Ding, R. Renegar, and Y.-H. Chen. 2015. A non-tight junction function of claudin-7 – Interaction with integrin signaling in suppressing lung cancer cell proliferation and detachment. Mol. Cancer. 14:120.

Lu, Z., L. Ding, Q. Lu, and Y.-H. Chen. 2013. Claudins in intestines: Distribution and functional significance in health and diseases. Tissue Barriers. 1: e24978.

Hoggard, J., J.M. Fan, Z. Lu, Q. Lu, L. Sutton, and Y.-H. Chen. 2013. Claudin-7 increases chemosensitivity to cisplatin through the upregulation of caspase pathway in human NCI-H522 lung cancer cells. Cancer Sci. 104: 611-618. (Editorial Highlight of this issue)

Ding, L., Z. Lu, Q. Lu, and Y.-H. Chen. 2013. The claudin family of proteins in human malignancy: A clinical perspective. Cancer Manag. Res. 5: 367-375.

Ding, L., Z. Lu, O. Foreman, R. Tatum, Q. Lu, R. Renegar, J. Cao, and Y.-H. Chen. 2012. Inflammation and disruption of the mucosal architecture in claudin-7-deficient mice. Gastroenterology. 142: 305-315. (Editorial highlight of this issue)

Lu, Z., L. Ding, H. Hong, J. Hoggard, Q. Lu, and Y.-H. Chen. 2011. Claudin-7 inhibits human lung cancer cell migration and invasion through ERK/MAPK signaling pathway. Exp. Cell Res. 317: 1395-1946.

Zhang, G, L. Ding, R. Renegar, X.M. Wang, Q. Lu, S.Q. Huo, and Y.-H. Chen. 2011. Hydroxycamptothecin-loaded Fe3O4 nanoparticles induce human lung cancer cell apoptosis through Caspase-8 pathway activation and disrupt tight junctions. Cancer Sci. 102: 1216-1222.

Tatum, R., Y. Zhang, K. Salleng, Z. Lu, J.-J. Lin, Q. Lu, B.G. Jeansonne, L. Ding, and Y.-H. Chen. 2010. Renal salt wasting and chronic dehydration in claudin-7-deficient mice. Am. J Physiol. Renal Physiol. 298: F24-34. (Editorial focus of this issue)

Chen, Y.-H., J-J. Lin, B.G. Jeansonne, R. Tatum, and Q. Lu. 2009. Analysis of claudin genes in pediatric patients with Bartter’s Syndrome. Ann. N. Y. Acad. Sci. 1165: 126-134.

Tatum, R., Y. Zhang, Q. Lu, K. Kim, B.G. Jeansonne, and Y.-H. Chen. 2007. WNK4 phosphorylates Ser206 of claudin-7 and promotes paracellular Cl- permeability. FEBS Lett. 581: 3887-3891.

Alexandre, M. D., B.G. Jeansonne, R.H. Renegar, R. Tatum, and Y.-H. Chen. 2007. The first extracellular domain of claudin-7 affects the paracellular Cl- permeability. Biochem. Biophys. Res. Commun. 357: 87-91.

Alexandre, M.D., Q. Lu, and Y.-H. Chen. 2005. Overexpression of claudin-7 decreases the paracellular Cl- conductance and increases the paracellular Na+ conductance in LLC-PK1 cells. J. Cell Science 118: 2683-2693.

Jeansonne, B., Q. Lu, D.A. Goodenough, and Y.-H. Chen. 2003. Claudin-8 interacts with multi-PDZ domain protein 1 (MUPP1) and reduces paracellular conductance in epithelial cells. Cell. Mol. Biol. 49: 13-21.

Chen, Y.-H., Q. Lu, D.A. Goodenough, and B. Jeansonne. 2002. Non-receptor tyrosine kinase c-yes interacts with occludin during tight junction formation in canine kidney epithelial cells. Mol. Biol. Cell. 13: 1227-1237.

Chen, Y.-H. and Q. Lu (equal contribution), E. Scheneeberg, and D. Goodenough. 2000. Restoration of junction assembly and barrier function by down regulation of MAP kinase pathway in ras-transformed MDCK cells. Molec. Biol. Cell 11: 849-862.

Merzdorf, C.S., Y.-H. Chen, and D.A. Goodenough. 1998. Formation of functional tight junctions in Xenopus embryos. Develop. Biol. 195: 187-203.

Chen, Y.-H., C.S. Merzdorf, D.L. Paul, and D.A. Goodenough. 1997. COOH terminus of occludin is required for tight junction barrier function in early Xenopus embryos. J. Cell Biol. 138: 891-899.

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Staff and Students

Location: 7N-55

Former Students and Post-Doctoral Fellows