Expression of Hedgehog Pathway Components is Associated with Bladder Cancer Progression and Clinical Outcome

Abstract

Hedgehog (Hh) pathway has been implicated in the tumorigenesis of a large number of human tumors. But its effects on the progression and prognosis of bladder cancer remain poorly understood. The aim of this study was to investigate expression patterns of Hh pathway components in bladder cancer and to elucidate their prognostic values in this tumor. The expression of sonic hedgehog (Shh), its receptor Patched (Ptch1), and downstream transcription factor Gli1 in 118 specimens of bladder cancer and 30 specimens of adjacent normal bladder tissue was determined by immunohistochemistry. Statistical analyses were applied to test the relationship between the expression of these three proteins and clinicopathologic features and prognosis. Immunohistochemical staining results showed the localizations of Shh and Ptch1 proteins to be mainly located in the cytoplasm of bladder cancer cells, whereas Gli1 was mainly localized in the nuclear of tumor cells. Additionally, positive expression of Shh, Ptch1 and Gli1 proteins was correlated with pathological stage (P = 0.006, 0.006 and 0.008, respectively), venous invasion (P = 0.01, 0.01 and 0.012, respectively) and lymph node metastasis (P = 0.009, 0.01 and 0.013, respectively), but not with other factors including age, gender, tumor grade and recurrence of superficial cancer. Moreover, patients with positive expression of Shh, Ptch1 and Gli1 proteins respectively showed poorer disease-free (P = 0.002, 0.002 and 0.001, respectively) and overall survival (all P < 0.001) than those with negative expression of these three proteins. Univariate and multivariate analysis of prognostic factors in bladder cancer patients indicated that the expression patterns of Shh, Ptch1 and Gli1 proteins were independent unfavorable prognostic factors (all P < 0.001). This is the first report describing about the correlation between Hh pathway and the prognosis of bladder cancer. Expression of Shh, Ptch1 and Gli1 proteins was greater in bladder cancers than in the adjacent normal tissues. The examination of their expression is potentially valuable in prognostic evaluation of bladder cancer.

Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients

“…SHH is active only in stem cells and/or endodermal progenitor in adults (16,23). Recent studies showed that aberrant signaling of this pathway is involved in a variety of human cancers (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). The HH pathway essentially consists of PTCH, the motive protein, SMOH, and the transcriptional factors GLI2 and GLI3.…”

“…The increased expression of GLI1 protein in breast tumor and hepatoblastoma is also reportedly correlated with significantly poor prognosis (24)(25)(26). The HH pathway mediates the progression of breast cancer from noninvasive to invasive and serves as a significant independent prognostic indicator in gastric and bladder cancers (27,28).…”

Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma

“…and T.Y.). For evaluation of Ptch, Smo, and Gli1 staining, an immunoreactivity score system was applied as described previously [20]. Cytoplasmic staining for Ptch, and cytoplasmic and nuclear staining for Smo and Gli1 were evaluated.…”

DHH is an Independent Prognosticator of Oncologic Outcome of Clear Cell Renal Cell Carcinoma

“…9 HH pathway reactivation was noted in different cancer entities such as ovarian, upper gastrointestinal tract and pancreatic cancer, 10e12 including urological malignancies of the prostate and bladder. 13,14 Some evidence suggests that the HH pathway may also have an important role in RCC. 15 We evaluated expression levels of 9 intermediates of the HH pathway by immunohistochemistry in a cohort of patients who underwent nephrectomy for RCC.…”