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Dai H. Chung, M.D.
Department of Surgery
Neuroblastoma is the most common extracranial solid
tumor in infants and children, and accounts for more than 15% of cancer-related deaths in
children. Despite recent advances in combined modality treatment, the overall mortality
for all stages of tumors remains significant at 50%. Unless the diagnosis is made at an
early age with localized disease, the cure for neuroblastoma remains dismal. As a
neuroendocrine tumor, neuroblastomas can produce various gastrointestinal (GI) hormones and the
amount of peptide expression has been associated with the clinical tumor behavior suggesting a
potential role for gut peptides as autocrine growth factors. Gastrin-releasing
peptide (GRP) is a gut/neuropeptide that stimulates the growth of normal and neoplastic tissues
and has also been found to be an autocrine growth factor for some cancers. Our studies
have identified an increased expression of GRP-receptors (GRP-R) in more aggressive
metastatic neuroblastomas in older children. Additionally, we have found that GRP
functionally couples to GRP-R to stimulate tumor growth, suggesting a role of GRP as an
autocrine growth factor for neuroblastomas.
Our ongoing projects include (1) characterizing
expression of GRP and GRP-R in various clinical stages of neuroblastomas, (2) determining
mechanisms involved in the regulation of GRP-R gene and protein expression, and (3) identifying
the role of phosphatidylinositol 3-kinase in GRP-induced proliferation of neuroblastomas.
Ethridge RT, Hashimoto K, Chung DH, Ehlers RA, Rajaraman S, Evers BM.
Selective inhibition of NF-kappaB attenuates the severity of cerulein-induced acute
pancreatitis. J Am Coll Surg 195:497-505, 2002.
Kim S, Hu W, Kelly DR, Hellmich MR, Evers BM, Chung DH. Gastrin-releasing peptide is a
growth factor for human neuroblastomas. Ann Surg 235:621-630, 2002.
Kim S, Domon-Dell C, Wang Q, Chung DH,
Cristofano AD, Pandolfi PP, Freund J-N, Evers BM. PTEN and TNF-a regulation of the intestinal-specific Cdx-2 homeobox gene through a PI3-K, PKB/Akt and NF-kB
dependent pathway. Gastroenterology 123:1163-1178, 2002.
Ethridge RT, Chung
DH, Slogoff M, Ehlers RA, Hellmich MR, Rajaraman S,
Saito H, Uchida T, Evers BM. Cyclooxygenase-2 gene disruption attenuates the severity of acute
pancreatitis and pancreatitis-associated lung injury. Gastroenterology 123:1131-1322, 2002.
Chappell VL, Thompson MD, Jeschke MG, Chung DH, Thompson JC, Wolf SE. Effects of
incremental starvation on gut mucosa. Dig Dis
Sci 48:765-9, 2003.
Kim S, Kang J, Hu W, Evers BM, Chung DH. Geldanamycin decreases Raf-1 and Akt levels and
induces apoptosis in neuroblastomas. Int J Cancer 103:352-359, 2003.
Kim S, Domon-Dell C, Kang J, Chung DH,
Freund J-N, Evers BM. Down-regulation of the tumor suppressor PTEN by the TNF-α/NIK/NF-kB
pathway is linked to a default IkB-α autoregulatory loop. J Biol Chem 279:4285-4291, 2004.
Qiao J, Cree J, Kang J, Kim S, Evers BM, Chung DH. Ets transcriptional
regulation of gastrin-releasing peptide receptor in neuroblastomas. Surgery 136:489-94, 2004.
Kim S, Kang J, Qiao J, Thomas RP, Evers BM, Chung DH.
Phosphatidylinositol 3-kinase inhibition down-regulates survivin and facilitates TRAIL-mediated
apoptosis in neuroblastomas. J Pediatr Surg 39:516-21, 2004.
Kim S, Kang J, Evers BM, Chung DH. Interferon-gamma induces caspase-8 in
neuroblastomas without affecting methylation of caspase-8 promoter. J Pediatr Surg 39:509-15, 2004.
Qiao J, Kang J, Cree J, Evers BM, Chung DH. Gastrin-releasing
peptide-induced down-regulation of tumor suppressor protein PTEN (phosphatase and tensin
homolog deleted on chromosome ten) in neuroblastomas. Ann Surg. 241:684-91; discussion 691-2, 2005.
Gustafson WC, De Berry BB, Evers BM, Chung DH. Role of gastrointestinal
hormones in neuroblastoma. World
J Surg. 29:281-6, 2005