Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a growing cause of cancer-related mortality worldwide. Kallikrein-related peptidase 8 (KLK8) has potential clinical values in many cancers. However, the clinicopathological significances of KLK8 in PDAC remain unknown. We explored the relationship of KLK8 to clinicopathological features of PDAC based on public databases. KLK8 expression was examined in human PDAC tissues. Cell proliferation and apoptosis were evaluated in KLK8-overexpressed human pancreatic cancer cell lines Mia-paca-2 and Panc-1. The related signaling pathways of KLK8 involved in pancreatic cancer progression were analyzed by gene set enrichment analysis (GSEA) and further verified in in vitro studies. We found that KLK8 was up-regulated in tumor tissues in the TCGA-PAAD cohort, and was an independent prognostic factor for both overall survival and disease-free survival of PDAC. KLK8 mRNA and protein expressions were increased in PDAC tissues compared with para-cancerous pancreas. KLK8 overexpression exerted pro-proliferation and anti-apoptotic functions in Mia-paca-2 and Panc-1 cells. GSEA analysis showed that KLK8 was positively associated with PI3K-Akt-mTOR and Notch pathways. KLK8-induced pro-proliferation and anti-apoptotic effects in Mia-paca-2 and Panc-1 cells were attenuated by inhibitors for PI3K, Akt, and mTOR, but not by inhibitor for Notch. Furthermore, overexpression of KLK8 in Mia-paca-2 and Panc-1 cells significantly increased epidermal growth factor (EGF) levels in the culture media. EGF receptor (EGFR) inhibitor could block KLK8-induced activation of PI3K/Akt/mTOR pathway and attenuate pro-proliferation and anti-apoptotic of KLK8 in Mia-paca-2 and Panc-1 cells. In conclusion, KLK8 overexpression exerts pro-proliferation and anti-apoptotic functions in pancreatic cancer cells via EGF signaling-dependent activation of PI3K/Akt/mTOR pathway. Upregulated KLK8 in PDAC predicts poor prognosis and may be a potential therapeutic target for PDAC.
Highlights
Pancreatic cancer is one of the most leading causes of cancer death in both males and females because of its poor prognosis, with almost as many deaths (n = 432,000) as cases (n = 459,000) [1]
Based on the indicated role of Kallikreinrelated peptidase 8 (KLK8) in malignant disease found in GEPIA (Figure 1A), we analyzed the expression of KLK8 in the independent public dataset from Oncomine and found that KLK8 expression was elevated in the pancreatic cancer tissue samples in comparison to the normal pancreas (Figure 1B, P
To further examine the potential relationship between KLK8 and Pancreatic Cancer (PAAD), we analyzed data from the TCGA-PAAD cohort which was replenished by GTEX database, and found that KLK8 was significantly upregulated in tumor tissues compared to normal tissues (Figure 1C, P
Summary
Pancreatic cancer is one of the most leading causes of cancer death in both males and females because of its poor prognosis, with almost as many deaths (n = 432,000) as cases (n = 459,000) [1]. According to 2020 cancer statistics, approximately 57,600 new cases of pancreatic cancer will be diagnosed, killing almost 47,050 people in the United States in 2020, making it the fourth leading cause of cancer-associated death [2]. Despite the advanced therapeutic approaches, the 5-year relative survival rate of pancreatic cancer remains poor, estimated at 9% [3,4,5]. To further improve the survival rates, it is critical to identify a more sensitive and effective biomarker associated with the tumorigenesis and progression for early detection, which will improve the prognosis for pancreatic cancer. The expression pattern and role of KLK8 in pancreatic cancer remains unknown
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