The main focus in Dr. Xie's laboratory is to investigate signal transduction of the hedgehog pathway and its role in the development of cancers. This pathway was initially discovered by two Nobel Laureates Dr. E. Wieschaus and Dr. C. Nusslein-Volhard in Drosophila in early 80's. The hedgehog signaling is a master regulator for cell differentiation, tissue polarity and cell proliferation. In the last few years, Dr. Xie and his colleagues have discovered two members of this pathway, patched and smoothened, being responsible for the development of basal cell carcinomas (BCCs) and medulloblastomas. BCCs, the most common cancer in Caucasians with the lifetime risk of one in three, are generally only locally invasive and rarely metastasized. Medulloblastomas, a primitive neuroectodermal tumor of cerebellum, account for 20% incidence of pediatric brain tumors, progress rapidly into malignant tumors. In these cancers, this pathway is activated by either inactivated mutations of patched or activated mutations of smoothened. Recent data indicate that hedgehog signaling is activated in about 30% extracutaneous tumors, including gastrointestinal, prostate and breast cancers. Whereas the biological consequences of dysregulation of this pathway are well established, the molecular mechanism of the signal transduction is still poorly understood. They are taking three approaches to understand the mechanism by which activation of the hedgehog pathway contributes to cancers. First, the activating form of smoothened or the downstream molecule Gli is used as a "biological probe" for the identification, isolation and functional dissection of molecular components that collaborate to regulate the signaling pathway. Second, they are studying the interaction of this pathway with other signaling pathways in human cancers. Third, mouse models are being used to understand activation of the hedgehog pathway in vivo. Ultimately, they hope to find ways to inhibit this pathway with small molecules in relevant human cancers.

Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn A, Myers RM, Cox DR, Epstein EH Jr, Scott MP.  Human homolog of PATCHED, a candidate gene for the basal cell nevus syndrome. Science 272:1668-1671, 1996.

Xie J, Murone M, Gu Q, Zhang C, Luoh S-M, Goddard A, Rosenthal A, Epstein EH Jr, de Sauvage FJ. Activating smoothened mutations in sporadic basal-cell carcinoma. Nature 391: 90-92, 1998.

Guo Q, Xie J, Dang CV, Liu ET, Bishop JM. Identification of a large Myc-binding protein that contains RCC1-like repeats. Proceeding of National Academy of Science 95:9172-917, 1998.

Lam CW, Xie J, To KF, Lee KC, Yuen WF, Lim PL, Chan YS, Tong SF, McCormick FA. frequent activated smoothened mutation in sporadic basal cell carcinomas.  Oncogene 18:833-837, 1999.

Xie* J, Aszterbaum M, Zhang X. Bonifas MB, Epstein EH Jr, McCormick F. The role of the Gli1 target gene PDGFRA in basal cell carcinoma proliferation. Proceeding of National Academy of Science 98:9255-9, 2001.

Lam C-W, Leung C-Y, Lee K-C, Xie J, Lo F-M, Au T-S, Tong S-F, Poon M-K, Chan L-Y and Luk, N-M, Novel mutations of the PATCHED gene in basal cell nevus syndrome. Molecular Genetics and Metablism 76:57-61, 2002.

Li C, He N, Zhang X, Wagner R, Tyring S, Xie* J.  IFNa induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling. Oncogene 23:1608-17, 2004.

Athar* M, Li C-X, Chi S, Tang X, Kim A-L, Norris BA, Tyring SK, Kopelovich L, Epstein EH Jr, Bickers DR, Xie* J.  Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through induction of fas expression and apoptosis (The first two authors contribute equally). Cancer Research 60:7545-52, 2004.   [Paper in PDF format]

Haque AK, Au W, Zwischenberger JB, Norris B, Ginzel AW, Jones DV, Xie J.  Association of patient smoking history, cyp2E1 polymorphism and p53 expression with patient survival in non-small cell lung cancer. American Immunohistochemistry and Molecular Morphology 12:315-322, 2004.    [Paper in PDF Format]

Sheng T,  Li C-X, Zhang X, Chi S, He N, Chen K, McCormick F, Gatalica Z, Xie* J.  Activation of the hedgehog pathway in advanced prostate cancer. Molecular Cancer 3:29, 2004.

He N, Li C-X, Zhang X, Sheng T, Chi S, Chen K, Wang Q, Vertrees R, Logrono R, Xie* J. Regulation of lung cancer cell invasion by β-TRCP. Molecular Carcinogenesis 42:18-28, 2005.

Ma, X.L., Chen, K., Huang S.H., Sheng, T., Zhang, X., Evers, B.M., Adegygoga, P., Zhang* H.W. and Xie* J (2005). Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas. Carcinogenesis 26(10):1698-1705. Epub 2005 May 19.

Ma, X.L., Sheng, T., Zhang, Y.X., Huang S.H., He, J., Chen, K., Zhang, X., Zhang* H.W. and Xie* J. Hedgehog signaling is activated in subsets of esophageal cancers. International Journal of Cancer 118(1):139-148, 2006. Epub 2005 July 7. 

Wickliffe JK, Galbert LA, Ammenheuser MM, Herring SM, Xie J, Masters III OE, Friedberg EC, Lloyd RS and Ward JB Jr. 3,4-Epoxy-1-butene, a reactive metabolite of 1,3-butadiene, induces somatic mutations in Xpc-null mice. Environ Mol Mutagen. 2005 Aug 10; [Epub ahead of print].

Vergrees RA, Das GC, Coscio AM, Xie J, Zwischenberger JB, Boor PJ. A mechanism of hyperthermia-induced apoptosis in ras-transformed lung cells. Mol Carcinog. 44(2):111-21, 2005.

Sheng T, Chi S, Zhang X and Xie* J, Regulation of Gli1 localization by the cAMP/ PKA signaling axis through a site near the nuclear localization signal. J. Biological Chemistry 2005 Nov. 17; [Epub ahead of time].

Chi S*, Huang S-H*, Zhang X, Li C-X, Haque AK, Zwischenberger J, Tyring SK, Logrono R, Bhutani M, Zhang H-W, Xie J. Expression of sonic hedgehog and its target genes in lung cancers. Cancer Lett 2006 Nov 28;244(1):53-60. Epub 2006 Jan 30.

Huang S*, He J*, Zhang X*, Bian X, Yang L, Xie G, Zhang K, Tang W, Stelter AA, Wang Q, Zhang HW, Xie J. Activation of the hedgehog pathway in human hepatocellular carcinomas. Carcinogenesis 27(7):1334-40 (Epub ahead of print on Feb. 25, 2006), 2006.

Ma XL, Sun HJ, Wang YS, Huang SH, Xie J, Zhang HW. Study of Sonic hedgehog signaling pathway related molecules in gastric carcinoma. World J Gastroenterol. 2006 Jul 7;12(25):3965-9.

He J, Sheng T, Stelter A, Li C, Zhang X, Sinha M, Luxon B, Xie J. Suppressing Wnt signaling by the hedgehog pathway through sFRP-1. J Biol Chem. 2006 Nov 24; 281(47):35598-602, 2006 Oct 10; [Epub ahead of print].

Tang WW, Stelter AA, French S, Shen S, Qiu S, Venegas R, Wen J, Wang H-Q and Xie J. Loss of Cell-Adhesion Molecule Complexes in Solid Pseudopapillary Tumor of Pancreas. Modern Pathology 20(5):509-13, 2007.

Bian Y, Huang S, Yang L, Ma X, Xie J and Zhang HW, The sonic hedgehog-Gli1 pathway in colorectal adenocarcinomas. World J Gastroenterol 13(11):1659-65, 2007.

Ji Z, Mei FC, Xie J, Cheng X., Oncogenic KRAS Activates Hedgehog Signaling Pathway in Pancreatic Cancer Cells. J Biol Chem. 282(19):14048-55, 2007.

Past Lab members: