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.
Background: Pure pancreatic-type ACC outside the pancreas is extremely rare. Methods: We presented a very rare case of primary ACC of the pancreatic-type involving jejunum with a synchronous metastasis to left adrenal gland arising in well-developed ectopic pancreas which had fully developed pancreatic acini, islets of Langerhans, ductal structures, pancreatic cancer precursor lesions and a well-formed minor papilla that opens to the mucosal surface of jejunum. We also reviewed all 21 cases of pure pancreatic-type ACC outside the pancreas in the literature. Results:The pre-operative diagnosis of pancreatic-type ACC outside the pancreas is challenging and difficult based on imaging studies or on small biopsies. Only 2 of 14 cases, which reported a pre-operative diagnosis, were correctly diagnosed as pancreatic-type ACC on liver biopsy. Patients who presented with unresectable or stage IV disease had mean overall survival of 13.5 (standard deviation *SD+, 4.2) months, which was shorter than those who underwent surgical resection with curative intent (mean: 54.3, *SD, 9.1+ months, P = 0.008). Conclusions:The pre-operative diagnosis of pancreatic-type ACC outside the pancreas is
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