Expression and prognostic value of tuberous sclerosis complex 2 gene product tuberin in human pancreatic cancer.
BACKGROUND
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutation of either of 2 tumor suppressor genes, TSC1 or TSC2, which encode hamartin and tuberin, respectively. Several studies have shown that tuberin functions independently of hamartin and inhibits signaling pathways via the mammalian target of rapamycin, a critical regulator of cell proliferation. Recent studies have revealed that the signaling pathways regulating the mammalian target of rapamycin such as Akt and S6K1 are frequently activated in pancreatic cancer. We hypothesized that tuberin might be involved in the proliferation and survival of pancreatic cancer cells.


METHODS
We immunohistochemically examined the expression of tuberin in 42 pancreatic cancerous and noncancerous pancreatic tissue specimens using an antituberin antibody. The correlations between tuberin expression and various clinicopathologic features, including survival, were evaluated. Reverse transcriptase-polymerase chain reaction was performed to evaluate the level of tuberin expression in paired samples of pancreatic cancer and noncancerous tissue.


RESULTS
Twenty-four of the 42 pancreatic cancer samples (57%) were negative for tuberin expression. The patients with tuberin-negative tumors had a significantly higher incidence of pT3 or pT4 disease (primary tumor extent by the TNM classification) than those with tuberin-positive tumors (P = .024). Female patients had a significantly higher incidence of tuberin-positive tumors than male patients (P = .014). The survival rate of the tuberin-positive group tended to be better than that of the tuberin-negative group, but there was no significant difference (P = .4). Expression of TSC2 in cancer tissue was lower than in the corresponding noncancerous tissue for 7 of the 9 samples examined.


CONCLUSIONS
This study demonstrates that reduced expression of tuberin might be involved in the progression of pancreatic cancer. Accordingly, tuberin may provide a new therapeutic target in patients with this type of cancer.
Kataoka
Kozo
K
Department of Surgery and Basic Surgical Science, Kyoto University, Japan.
Fujimoto
Koji
K
Ito
Daisuke
D
Koizumi
Masayuki
M
Toyoda
Eiji
E
Mori
Tomohiko
T
Kami
Kazuhiro
K
Doi
Ryuichiro
R
D000368:Aged; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D012097:Repressor Proteins; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins