Sp1, a New Biomarker That Identifies a Subset of Aggressive Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic adenocarcinoma is one of the leading causes of cancer-related deaths in the United States. Sp1 is a sequence-specific DNA binding protein that is important in the transcription of a number of regulatory genes involved in cancer cell growth, differentiation, and metastasis. In this study, we investigated Sp1 expression in pancreatic ductal adenocarcinoma and its association with clinical outcome. We studied 42 patients with primary pancreatic adenocarcinoma. The expression of Sp1 in pancreatic adenocarcinoma was evaluated by immunohistochemical staining. All 42 patients had clinical follow-up information and were evaluated for survival. Sp1 protein was aberrantly overexpressed in a subset of primary pancreatic adenocarcinoma. These tumors all developed metastasis, whereas none of the primary tumors without lymph node metastasis showed Sp1 overexpression. Statistically, Sp1 overexpression was associated with higher stage, higher grade, and lymph node metastasis (P < 0.001, P = 0.036, and P < 0.0001, respectively). Additionally, patients of this subset had a much shorter overall survival than patients without Sp1 overexpression, as evidenced by Kaplan-Meier plots and the log-rank test (P = 0.002). The 5-year overall survival rate was 19% in patients with Sp1 overexpression, compared with 55% in patients without Sp1 overexpression. The median survival was only 13 months for patients with Sp1 overexpression, compared with 65 months for patients without Sp1 overexpression. In conclusion, Sp1 is a new biomarker that identifies a subset of pancreatic ductal adenocarcinoma with aggressive clinical behavior. It can be used at initial diagnosis of pancreatic adenocarcinoma to identify patients with an increased probability of cancer metastasis and much shortened overall survival.

Triptolide-induced Cell Death in Pancreatic Cancer Is Mediated by O-GlcNAc Modification of Transcription Factor Sp1

“…Lines of evidence demonstrate that overactivation of Sp1 occurs frequently in a wide variety of human tumors, including pancreatic cancer, and that high Sp1 expression correlates with aggressive biology and poor clinical outcome (15,16). Sp1 has also been shown to be overexpressed in pancreatic tumors (17,18).…”

Mechanism of Metformin-dependent Inhibition of Mammalian Target of Rapamycin (mTOR) and Ras Activity in Pancreatic Cancer

“…The importance of targeting Sp transcription factors in pancreatic cancer was confirmed by knockdown of Sp1, which resulted in inhibition of growth and invasion and induction of apoptosis (49). Moreover, high Sp1 expression in pancreatic tumors is a prognostic factor for decreased pancreatic cancer patient survival (50). It has also been reported that knockdown of Sp1, Sp3, and Sp4 also decreased expression of receptor tyrosine kinases and phosphorylation of other kinases such as AKT (39), and in this study, we initially investigated the role of metformin-induced downregulation of Sp transcription factors on the mTOR pathway.…”

Methyl 2-Cyano-3,12-dioxooleana-1,9-dien-28-oate Decreases Specificity Protein Transcription Factors and Inhibits Pancreatic Tumor Growth: Role of MicroRNA-27a

“…Several reports show that Sp1 protein is overexpressed in different human tumor types, including gastric, colorectal, pancreatic, epidermal, thyroid, and breast cancers (Zannetti et al, 2000;Shi et al, 2001;Chiefari et al, 2002;Wang et al, 2003;Hosoi et al, 2004;Yao et al, 2004;Mertens-Talcott et al, 2007;Jiang et al, 2008). In patients with gastric cancer, there was an association between Sp1 expression with advanced stage of the tumor, VEGF expression, and poor survival (Yao et al, 2004).…”