Elevated expression of KLK8 predicts poor prognosis in colorectal cancer

Liu, Xianwu; Quan, Bin; Tian, Zhilong; Xi, Hailin; Jia, Gaolei; Wang, Hui; Zhang, Liang; Liu, Ruming; Ma, Cheng; Han, Fuzhou; Li, Huansong; Yuan, Feifei

doi:10.1016/j.biopha.2017.01.112

Cited by 19 publications

(15 citation statements)

References 20 publications

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“…KLK6 mRNA overexpression evokes a poor prognosis in the colon cancer patient cohort 43 . Moreover, elevated KLK8 mRNA and protein level are detected in CRC tissue, which leads to an aggressive phenotype and poor prognosis 44 . The expression level of KLK10 is significantly higher in ovarian, pancreatic and colon cancer compared to normal tissues 23 , 45 , 46 .…”

Section: Discussionmentioning

confidence: 99%

Identification and pharmaceutical evaluation of novel frog skin-derived serine proteinase inhibitor peptide–PE-BBI (Pelophylax esculentus Bowman-Birk inhibitor) for the potential treatment of cancer

Lyu¹,

Ma³

et al. 2018

Sci Rep

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Amphibian venom-derived peptides have high potential in the field of anticancer drug discovery. We have isolated a novel Bowman-Birk proteinase inhibitor (BBI)-type peptide from the skin secretion of Pelophylax esculentus (PE) named PE-BBI, and evaluated its bio-functions and anti-cancer activity in vitro. PE-BBI is a heptadecapeptide with C-terminal amidation. The mRNA sequence and primary structure of PE-BBI were identified using RT-PCR and LC/MS, respectively. A trypsin inhibitory assay was used to characterize the serine proteinase inhibitory activity of synthetic PE-BBI. PE-BBI’s myotropic activity was analyzed using isolated rat bladder and rat-tail artery smooth muscle tissues, and the anti-cancer ability of PE-BBI using human colorectal cancer cells. PE-BBI’s mechanism of action was investigated using Discovery studio software. PE-BBI showed trypsin inhibitory activity (Ki = 310 ± 72 nM), strong myotropic activity, and cytotoxicity that were specific to cancer cells, and no side effect to normal epithelial cells. The docking stimulation showed that PE-BBI had high affinity to several members of human kallikrein related peptidase (KLK) family. This finding helps to enrich our understanding of BBI peptides’ mode of action. Moreover, the data presented here validates frog secretions as sources of potential novel proteinase inhibitors for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Identification and pharmaceutical evaluation of novel frog skin-derived serine proteinase inhibitor peptide–PE-BBI (Pelophylax esculentus Bowman-Birk inhibitor) for the potential treatment of cancer

Lyu¹,

Ma³

et al. 2018

Sci Rep

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“… 9 Previous studies have shown that KLK11 is expressed in human brain, skin, gastric, breast, prostate, ovarian, and intestinal tissues. 10 – 15 Alexopoulou et al 16 demonstrated that the expression of KLK11 mRNA was upregulated and it could be used as a novel prognostic biomarker of CRC, whereas Talieri et al did not provide similar results. 17 In our previous study, we have identified that the differential mRNA expression of KLK11 was associated with chemosensitivity in patients with CRC.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of KLK11 reverses oxaliplatin resistance by inhibiting proliferation and activating apoptosis via suppressing the PI3K/AKT signal pathway in colorectal cancer cell

Zhang¹,

Xu²,

Sun³

et al. 2018

OTT

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IntroductionKallikrein 11 (KLK11) plays a crucial role in drug-resistance to oxaliplatin (L-OHP) in the treatment of metastatic colorectal cancer (mCRC). The study aimed to investigate the role of KLK11 in chemoresistance, and to clarify the mechanism underlying reverse of L-OHP resistance by knockdown of KLK11.Materials and MethodsResistance to oxaliplatin was induced in HCT-8 (HCT-8/L-OHP) colorectal adenocarcinoma cell lines by exposing cells to increasing concentrations of L-OHP. MTT, RT-qPCR, and Western blot were used to evaluate the resistance to L-OHP. We then knocked down KLK11 in HCT-8/L-OHP cells to explore the mechanism through which KLK11 reverses L-OHP resistance. The mRNA and protein expression of KLK11 in tissues from mCRC patients were detected by RT-qPCR and immunohistochemistry.ResultsThe drug resistance index (RI) of HCT-8/L-OHP cell line to L-OHP, 5-Fluorouracil (5-FU), Irinotecan (CPT-11), Vincristine (VCR) and Cis-diamminedichloroplatinum (CDDP) were 10, 5.35, 3.23, 1.28, and 6.64, respectively. Increased expression of multi-drug resistant genes ABCC1, ABCB1, GSTP1 and ERCC1 were detected in HCT-8/L-OHP cell line. Moreover, the activated PI3K/AKT pathway was related to L-OHP-resistance. Knockdown of KLK11 in HCT-8/L-OHP cell reversed L-OHP-resistance by inhibiting cell growth and activating apoptosis via suppressing the PI3K/AKT signaling pathway. Moreover, high expression of KLK11 in chemoresistant-patients was associated with lymph node metastases and histopathology.ConclusionKLK11 was highly expressed in chemoresistant-patients and L-OHP-resistant cell lines. Moreover, L-OHP resistance was associated with activated PI3K/AKT signal pathway. Knockdown of KLK11 can reverse L-OHP resistance by blocking PI3K/AKT signaling pathway.

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“…Tissue kallikrein-related peptidases (KLKs) are a group of serine proteases encoded by 15 highly conserved trypsin-or chymotrypsin-like serine proteases displaying diverse biological processes, such as embryogenesis and pregnancy, blood coagulation, complement activation, general protein turnover and wound healing. [6][7][8][9]. KLK8, an important member of the KLKs family, is a synaptic, plasticity-modulating extracellular serine protease and has been found in many tissues and biological uids, involved in a variety of biological activities, for instance, epidermal proliferation and differentiation, terminal differentiation of keratinocytes and so on [10,11].…”

Section: Introductionmentioning

confidence: 99%

Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

Hua

Liu

et al. 2020

Preprint

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Background: 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. Methods: The relationship of KLK8 to clinicopathological features of PDAC was investigated 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. Results: 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.Conclusion: KLK8 overexpression exerts pro-proliferation and anti-apoptotic functions in pancreatic cancer cells via PI3K/Akt/mTOR pathway. Upregulated KLK8 in PDAC predicts poor prognosis and may be a potential therapeutic target for PDAC.

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Elevated expression of KLK8 predicts poor prognosis in colorectal cancer

Cited by 19 publications

References 20 publications

Identification and pharmaceutical evaluation of novel frog skin-derived serine proteinase inhibitor peptide–PE-BBI (Pelophylax esculentus Bowman-Birk inhibitor) for the potential treatment of cancer

Identification and pharmaceutical evaluation of novel frog skin-derived serine proteinase inhibitor peptide–PE-BBI (Pelophylax esculentus Bowman-Birk inhibitor) for the potential treatment of cancer

Knockdown of KLK11 reverses oxaliplatin resistance by inhibiting proliferation and activating apoptosis via suppressing the PI3K/AKT signal pathway in colorectal cancer cell

Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

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