Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

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.

Optimization of a mouse model of pancreatic cancer to simulate the human phenotypes of metastasis and cachexia

“…1 C and D; FDR of < 0.05 and a fold cutoff of 1.5-fold). Three of the highest upregulated DEGs from KPCML1 cells, Hyaluronan Synthase 1 ( Has1 ), S ynaptotogmin 8 ( Syt8 ), and Kallikrein-8 ( Klk8 ), have been associated with the progression of PDAC [ 39 – 41 ]. The upregulation of these three genes were further confirmed by qRT-PCR (Fig.…”

A KLK6 Activity-Based Probe Reveals a Role for KLK6 Activity in Pancreatic Cancer Cell Invasion

“…KLK6 was found to be active in this cell line, consistent with mRNA expression data (Figure S1) providing a model for selective KLK6 ABP development. Since KLK8 is typically co-expressed with KLK6 in multiple disease contexts, including in pancreatic cancer, ,− initial probe development focused on an ABP selective toward KLK6 over KLK8, a challenging objective in view of their common trypsin-like specificity for Lys/Arg at P1.…”

Distinct cell states define the developmental trajectories of mucinous appendiceal neoplasms towards pseudomyxoma metastases

“…KLK8 has high expression in a variety of tumors including pancreatic and colorectal cancer. In experimental mouse models, KLK8 overexpression had both pro-proliferative and anti-apoptotic effects [49, 50]. The FKBP4 gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking.…”

“…KLK8 is highly expressed in several tumor types including pancreatic and colorectal cancer. In mouse models, KLK8 overexpression had pro-proliferative and anti-apoptotic effects (34). FKBP4 belongs to the immunophilin family with roles in immunoregulation, protein folding and trafficking.…”