Prognostic and Functional Significance of MAP4K5 in Pancreatic Cancer

Abstract

ObjectivesMAP4K5 plays an important role in regulating a range of cellular responses and is involved in Wnt signaling in hematopoietic cells. However, its functions in human malignancies have not been studied. The major objectives of this study are to examine the expression, functions and clinical significance of MAP4K5 in pancreatic ductal adenocarcinoma (PDAC).Materials and MethodsThe expression levels of MAP4K5, E-cadherin, vimentin, and carboxylesterase 2 (CES2) were examined by immunohistochemistry in 105 PDAC and matched non-neoplastic pancreas samples from our institution. The RNA sequencing data of 112 PDAC patients were downloaded from the TCGA data portal. Immunoblotting and RNA sequencing analysis were used to examine the expression of MAP4K5 and E-cadherin in pancreatic cancer cell lines. The effect of knockdown MAP4K5 using siRNA on the expression of CDH1 and vimentin were examined by Real-time RT-PCR in Panc-1 and AsPC-1 cells. Statistical analyses were performed using IBM SPSS Statistics.ResultsMAP4K5 protein is expressed at high levels specifically in the pancreatic ductal cells of 100% non-neoplastic pancreas samples, but is decreased or lost in 77.1% (81/105) of PDAC samples. MAP4K5-low correlated with the loss of E-cadherin (P = 0.001) and reduced CES2 expression (P = 0.002) in our patient populations. The expression levels of MAP4K5 mRNA directly correlated with the expression levels of CDH1 mRNA (R = 0.2490, P = 0.008) in the second cohort of 112 PDAC patients from The Cancer Genome Atlas (TCGA) RNA-seq dataset. Similar correlations between the expression of MAP4K5 and E-cadherin were observed both at protein and mRNA levels in multiple pancreatic cancer cell lines. Knockdown MAP4K5 led to decreased CDH1 mRNA expression in Panc-1 and AsPC-1 cells. MAP4K5-low correlated significantly with reduced overall survival and was an independent prognosticator in patients with stage II PDAC.ConclusionsMAP4K5 expression is decreased or lost in majority of PDACs. The strong associations between low MAP4K5 expression and loss of E-cadherin, reduced CES2 expression and decreased overall survival may suggest an important role of MAP4K5 in epithelial-to-mesenchymal transition, chemotherapy resistance and tumor progression in pancreatic cancer. Targeting impaired MAP4K5 signaling may represent a new therapeutic strategy for pancreatic cancer.

Hippo pathway affects survival of cancer patients: extensive analysis of TCGA data and review of literature

“… 28 protein 66 0.025 0.025 high median SEP as cutoff MAP4K5 pancreatic cancer Wang OH et al . 29 protein 105 0.02 0.012 low negative or weak staining vs moderate or strong staining MOB1A intrahepatic cholangiocarcinoma Sugimachi K et al . 30 protein 88 0.0202 n.s.…”

Prognostic Evaluation of Vimentin Expression in Correlation with Ki67 and CD44 in Surgically Resected Pancreatic Ductal Adenocarcinoma

“…New molecular markers are under investigation aiming at implementing targeted therapies in the future. The authors are planning to proceed with a new prospective trial on PDAC patients, regarding the expression of MAP4K5, which started being studied very recently [ 29 ].…”

Identification of a dual TAOK1 and MAP4K5 inhibitor using a structure-based virtual screening approach

“…To explore common interactions between the three active compounds, we compared their interactions in both MAP4K5 and TAOK1 binding site. Both MAP4K5 and TAOK1 are grouped in the STE20 kinases 19,20 . This suggests that the two target kinases may share common characteristics within the ATP-binding site.…”

“…Both MAP4K5 and TAOK (Thousand-and-one amino acid kinase) belong to the mammalian STE20 kinase family 19,20 . MAP4K5, also named kinase homologous to STE20 (KHS1) or germinal centre kinase related (GCKR), phosphorylates various downstream kinase cascades, such as MKK4/MKK7, c-Jun N-terminal kinase (JNK) and stress-activated protein kinase (SAPK) cascades 21 .…”

“…Irregular expression of these two kinases have been linked to various diseases. MAP4Ks were reported to modulate tumour cell transformation, invasion, and adhesion 20,24 . Overexpression of MAP4K5 has been linked to acute myeloid leukaemia 25 and MAP4K5 has prognostic and functional significance in cancer.…”