p38delta/MAPK13 as a diagnostic marker for cholangiocarcinoma and its involvement in cell motility and invasion

Abstract

Cholangiocarcinoma (CC) and hepatocellularcarcinoma (HCC) are two main forms of liver malignancies, which exhibit differences in drug response and prognosis. Immunohistotochemical staining for cytokeratin markers has been used to some success in the differential diagnosis of CC from HCC. However, there remains a need for additional markers for increased sensitivity and specificity of diagnosis. In this study, we have identified a p38 MAP kinase, p38d (also known as MAPK13 or SAPK4) as a protein that is upregulated in CC relative to HCC and to normal biliary tract tissues. We performed microarray gene expression profiling on 17 cases of CC, 12 cases of adjacent normal liver tissue, and three case of normal bile duct tissue. p38d was upregulated in 16 out of 17 cases of CC relative to normal tissue. We subsequently performed immunohistochemical staining of p38d in 54 cases of CC and 54 cases of HCC. p38d staining distinguished CC from HCC with a sensitivity of 92.6% and a specificity of 90.7%. To explore the possible functional significance of p38d expression in CC, we examined the effects of overexpression and knockdown of p38d expression in human CC cell lines. Our results indicate that p38d is important for motility and invasion of CC cells, suggesting that p38d may play an important role in CC metastasis. In summary, p38d may serve as a novel diagnostic marker for CC and may also serve as a new target for molecular based therapy of this disease.

IL-13–induced airway mucus production is attenuated by MAPK13 inhibition

“…The relatively unstudied MAPK13 was originally described as responsive to inflammatory cytokines and cellular stress but downstream targets were uncertain (49). Subsequent reports suggested a role for MAPK13 in keratinocyte differentiation and survival (50,51), microtubule assembly and neurogeneration (52), attenuation of insulin secretion (53), and cell proliferation in skin cancer and cholangiocarcinoma (54,55); however, no complete scheme has emerged for MAPK13 activity in human disease. Instead, most previous work has concentrated on other MAPK family members, primarily MAPK14, as contributing to inflammation in the airway and other sites (56) as well as driving mucus production (12,26).…”

Current Management of Perihilar Cholangiocarcinoma and Future Perspectives

“…Systematic reviews and meta-analyses of IHC performed in resected CCA has demonstrated an association of the patients' postoperative survival with markers for fascin, VEGF-A, c-erbB-2, EGFR, MUC1, MUC4, p38delta and p27. Marker expression may also vary between iCCA and extrahepatic CCA, which further confirms the biologically distinct behavior of these lesions (29)(30)(31). While nodal metastasis typically occurs via perineural and periductal lymphatic channels and distal metastasis occur via the hematogenous route, local progression of pCCA usually occurs through intrahepatic ductal extension.…”

“…MLL3, ROBO2, RNF43, PEG3, and GNAS) were significantly different than non-infectious CCA (e.g. BAP1, IDH1 and IDH2) (30,31). TP53 and KRAS mutations are frequently seen in CCA patients from all geographic regions including Asia, Europe and the United States.…”

Pathogenesis of cholangiocarcinoma: From genetics to signalling pathways

“…Mitogen-activated protein kinases (MAPKs) signaling, for example, modulates oncogenic activity with promoting proliferation, invasion, inflammation, and angiogenesis in cancers including CCA. p38delta has been proposed as a specific biomarker for CCA which is overexpressed at both the RNA and protein levels in CCA tumours compared to HCC or normal liver tissue [89]. Recently, ERBB2 and MET oncogenes showed upregulated levels in CCA tumour and positive ERBB2 cases are highly correlated with lymph node metastasis [90].…”