p38delta/MAPK13 as a diagnostic marker for cholangiocarcinoma and its involvement in cell motility and invasion†
Felicia Li-Sher Tan
Department of General Surgery, Singapore General Hospital, Singapore
Department of Surgical Oncology, National Cancer Centre, Singapore
NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore
The first three authors contributed equally to this work
Search for more papers by this authorAikseng Ooi
NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore
Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan
The first three authors contributed equally to this work
Search for more papers by this authorDachuan Huang
NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore
The first three authors contributed equally to this work
Search for more papers by this authorJing Chii Wong
NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore
Search for more papers by this authorChao-Nan Qian
NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore
Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan
Search for more papers by this authorCora Chao
Department of Pathology, Singapore General Hospital, Singapore
Search for more papers by this authorLondon Ooi
Department of Surgical Oncology, National Cancer Centre, Singapore
Search for more papers by this authorYu-Meng Tan
Department of Surgical Oncology, National Cancer Centre, Singapore
Search for more papers by this authorAlexander Chung
Department of General Surgery, Singapore General Hospital, Singapore
Search for more papers by this authorPeng-Chung Cheow
Department of General Surgery, Singapore General Hospital, Singapore
Search for more papers by this authorZhongfa Zhang
Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan
Search for more papers by this authorDavid Petillo
Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan
Search for more papers by this authorXiming J. Yang
Department of Pathology, Northwestern University, Chicago, Illinois
Search for more papers by this authorCorresponding Author
Bin Tean Teh
NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore
Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan
Tel: 616-234-5296
Laboratory of Cancer Genetics, Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USASearch for more papers by this authorFelicia Li-Sher Tan
Department of General Surgery, Singapore General Hospital, Singapore
Department of Surgical Oncology, National Cancer Centre, Singapore
NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore
The first three authors contributed equally to this work
Search for more papers by this authorAikseng Ooi
NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore
Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan
The first three authors contributed equally to this work
Search for more papers by this authorDachuan Huang
NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore
The first three authors contributed equally to this work
Search for more papers by this authorJing Chii Wong
NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore
Search for more papers by this authorChao-Nan Qian
NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore
Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan
Search for more papers by this authorCora Chao
Department of Pathology, Singapore General Hospital, Singapore
Search for more papers by this authorLondon Ooi
Department of Surgical Oncology, National Cancer Centre, Singapore
Search for more papers by this authorYu-Meng Tan
Department of Surgical Oncology, National Cancer Centre, Singapore
Search for more papers by this authorAlexander Chung
Department of General Surgery, Singapore General Hospital, Singapore
Search for more papers by this authorPeng-Chung Cheow
Department of General Surgery, Singapore General Hospital, Singapore
Search for more papers by this authorZhongfa Zhang
Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan
Search for more papers by this authorDavid Petillo
Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan
Search for more papers by this authorXiming J. Yang
Department of Pathology, Northwestern University, Chicago, Illinois
Search for more papers by this authorCorresponding Author
Bin Tean Teh
NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore
Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan
Tel: 616-234-5296
Laboratory of Cancer Genetics, Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USASearch for more papers by this authorThis paper is dedicated to the memory of Connie Low and Christian Helmus
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, p38δ (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. p38δ was upregulated in 16 out of 17 cases of CC relative to normal tissue. We subsequently performed immunohistochemical staining of p38δ in 54 cases of CC and 54 cases of HCC. p38δ staining distinguished CC from HCC with a sensitivity of 92.6% and a specificity of 90.7%. To explore the possible functional significance of p38δ expression in CC, we examined the effects of overexpression and knockdown of p38δ expression in human CC cell lines. Our results indicate that p38δ is important for motility and invasion of CC cells, suggesting that p38δ may play an important role in CC metastasis. In summary, p38δ may serve as a novel diagnostic marker for CC and may also serve as a new target for molecular based therapy of this disease.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
|---|---|
| IJC_24944_sm_SuppFig1.tif20.9 MB | Supporting Information Figure 1. Knockdown of p38δ inhibits cell migration in a wound healing assay. Knockdown of p38δ in EGI-1 cells (a) and TGBC1TKB cells (b) by siRNA and effects on wound healing. The cells were maintained for 10 to 15 hours to assess cell migration into the wound. The wound healing ability of experimental samples (right panels) were significantly lower than controls (left panels). (Bar=500μm) |
| IJC_24944_sm_SuppFig2.tif14.1 MB | Supporting Information Figure 2. Knockdown of p38δ has no effect on cell proliferation. Knockdown of p38δ in EGI-1 cells (a) and TGBC1TKB cells (b) by siRNA. The number of cells was determined by Trypan exclusive counting. The results represent means ±S.D. of triplicates. Knockdown samples showed no statistical differences from controls, p>0.05. |
| IJC_24944_sm_SuppTable1.doc34.5 KB | Supporting Information Table 1. HISTOPATHOLOGICAL INFORMATION ON ALL CHOLANGIOCARCINOMA CASES USED IN THIS STUDY. |
| IJC_24944_sm_SuppTable2.doc32 KB | Supporting Information Table 2. DIFFERENTIATION GRADE INFORMATION ON ALL HCC PATIENT SAMPLES USED IN THIS STUDY. |
| IJC_24944_sm_SuppMaterials.doc25.5 KB | Supporting Information Materials. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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