Decreased TIP30 expression predicts poor prognosis in pancreatic cancer patients

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is known for its aggressive growth, and is characterized by early tissue invasion and metastasis with poor prognosis. Identifying prognostic markers and delineating the underlying mechanisms that promote progression of PDAC are important for the treatment of pancreatic cancer. TIP30, a newly identified tumor suppressor, appears to be involved in multiple processes during tumor development and metastasis. Here, we investigated the expression of TIP30 in PDAC and its prognostic value in PDAC patients. We examined the expression of TIP30 by immunohistochemistry in tissue microarrays containing 106 surgically resected PDAC. Kaplan-Meier analysis and Cox proportional hazards regression modeling analysis showed that TIP30 expression independently predicted better survival in pancreatectomy patients (p < 0.01). Moreover, decreased TIP30 expression was associated with lymph node metastasis (p < 0.05) and loss of E-cadherin expression (r 5 0.329, p < 0.01). Suppression of TIP30 resulted in upregulation of Snail and subsequent downregulation of E-cadherin in SW1990 cells containing high-level of endogenous TIP30. However, in the PANC-1 cells containing low level of endogenous TIP30, suppressing TIP30 caused upregulation of Slug instead of Snail, followed by upregulation of MMP9 rather than E-cadherin. Taken together, our work reveals that decreased TIP30 expression is able to enhance invasion and metastasis of pancreatic cancer cells through upregulation of the Snail family members and may serve as an independent predictor for poor outcomes in PDAC patients.TIP30, also known as CC3 or HTATIP2, is a 30-kDa human cellular protein that was purified as a HIV-1 Tat-interacting protein.1 Its expression is altered in human liver, lung, breast, gallbladder, colorectal and gastric cancers.2-7 Data from these studies showed that deficiency in TIP30 facilitated tumorigenesis, invasion and metastasis, suggesting that TIP30 may act as a tumor suppressor. TIP30 may function as a transcription cofactor to suppress the expression of genes that are involved in proliferation, apoptosis and angiogenesis. [8][9][10] Recently, downregulation of the EGFR signaling pathway by TIP30 was elucidated in breast cancer and hepatocellular carcinoma. 11,12 In addition, the relationship between TIP30 and the critical metastasis-associated protein, osteopontin and matrix metalloproteinases (MMPs) has been demonstrated previously.

Tat-Interacting Protein 30 (TIP30) Expression Serves as a New Biomarker for Tumor Prognosis: A Systematic Review and Meta-Analysis

“…TIP30 is involved in the control of cell apoptosis, growth, metastasis, angiogenesis, DNA repair, and tumor cell metabolism [11]. TIP30 has been found to be expressed in a wide variety of tumor tissues, including esophageal carcinoma [12], laryngeal carcinoma [13], glioma [14], pancreatic ductal adenocarcinoma [15], breast cancer [16], gastric cancer [17], gallbladder adenocarcinoma [18], lung cancer [19], and hepatocellular carcinoma [20]. The methylation of the TIP30 promoter may also be associated with tumor prognosis [21], but there are conflicting results from another study [22].…”

TIP30 regulates lipid metabolism in hepatocellular carcinoma by regulating SREBP1 through the Akt/mTOR signaling pathway

“…TIP30 is an important prognostic predictor for various cancers. 19, 48, 49 Upregulated SREBP1 associated with a poor prognosis of HCC patients. 50 Remarkably, when the combined effects of TIP30 and SREBP1 were evaluated, the sensitivity for survival analysis of HCC patients was improved.…”

“…12, 13, 14, 15, 16, 17, 18 Moreover, we also found downregulated TIP30 induces epithelial–mesenchymal transition in HCC and pancreatic cancer. 19, 20 …”

TIP30 inhibits oligodendrocyte precursor cell differentiation via cytoplasmic sequestration of Olig1

“…Several transcription factors have been identified as essential in oligodendrocyte development (Li et al, ; Wegner, ), such as Olig1 and Olig2, which play essential roles in oligodendrocyte specification and maturation (Lu et al, ; Takebayashi et al, ; Zhou et al, ). In this study, we have defined a crucial role for TIP30, a cytosolic protein that has been correlated with tumorigenesis and tumor metastasis (Guo et al, ; Kumtepe et al, ; Li et al, ; Tong et al, ), in regulating OL differentiation. We found that TIP30 was expressed in all oligodendrocyte lineage stages and was significantly down‐regulated from 2–3 weeks postnatal, a period critical for myelin formation (Chen et al, ), suggesting that it may serve as an OPC differentiation inhibitor.…”