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A High Level of Integrin α6 Expression in Human Intrahepatic Cholangiocarcinoma Cells Is Associated with a Migratory and Invasive Phenotype

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Abstract

Background

The integrin α6 subunit is part of the integrin α6β1 and α6β4 complexes, which are known to mediate the invasion of carcinoma cells. However, the precise role of integrin α6 in intrahepatic cholangiocarcinoma (ICC) has not yet been addressed.

Methods

Twenty cases of ICCs and matched nontumor samples were used to analyze integrin α6 expression by immunohistochemistry. After the expression of integrin α6 was determined by RT-PCR and Western blot in ICC cells, we regulated the expression of integrin α6 in ICC cells with specific vshRNA-integrin α6, and assessed the role of integrin α6 in the proliferation and metastasis/invasion of ICC cells. Finally, the involved mechanisms and clinical significance were further investigated.

Results

The expression of integrin α6 in ICC tissues was much higher than that in nontumor samples, and the high level of integrin α6 was detected in ICC cells compared with normal liver cells and HepG2 cells. After the down-regulation of integrin α6 in HCCC-9810 cells, we showed that the ability of ICC cells to metastasize and invade was much decreased in vitro, and cell proliferation was inhibited significantly. Further study indicated high expression of integrin α6 enhanced the activation of ERK1/2 and AKT signals in ICC cells and the inhibition of ERK1/2 down-regulated ICC cell proliferation, while the inhibition of AKT markedly impaired ICC cell metastasis and invasion. Integrin α6 overexpression was significantly correlated with larger tumors, multiple nodular, microvascular/bile duct invasion, and lymphatic metastasis (p < 0.05). The postoperative 5-year overall survival (OS) rate in patients with integrin α6low was higher than that of the integrin α6high group.

Conclusions

Overexpression of integrin α6 is associated with a migratory and invasive phenotype of ICC, and integrin α6 may be used as molecular target for therapy of ICC.

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Abbreviations

ICC:

Intrahepatic cholangiocarcinoma

PLC:

Primary liver cancer

IHC:

Immunohistochemistry

ECM:

Extracellular matrix

DMEM:

Dulbecco’s modified Eagle’s medium

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

H&E:

Hematoxylin and eosin

HCC:

Hepatocellular carcinoma

RNAi:

RNA interference

shRNA:

Short hairpin RNA

ERK:

Extracellular regulated protein kinase

PKB:

Protein kinase B

PI3 K:

Phosphatidylinositol-3-kinase

RT-PCR:

Reverse transcription polymerase chain reaction

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (81260321) and the National Natural Science Foundation of Hainan Province (No. 811206).

Conflict of interest

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Authors and Affiliations

  1. Department of Gastroenterology, Yangzhou No. 1 People’s Hospital, The Second Clinical School of Yangzhou University, Yangzhou, 225000, People’s Republic of China

    Yan-bing Ding, Bin Deng, Wei-ming Xiao, Jian Wu, Yuan-zhi Wang, Da-cheng Wu, Guo-tao Lu & Ke-yan Wu

  2. Department of Pathology, Hainan Medical University, Haikou, 571101, People’s Republic of China

    You-sheng Huang

  3. The Medical College of Yangzhou University, Yangzhou, 225000, People’s Republic of China

    Yan-qing Zhang

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  1. Yan-bing Ding
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  2. Bin Deng
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  4. Wei-ming Xiao
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  5. Jian Wu
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  7. Yuan-zhi Wang
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  9. Guo-tao Lu
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  10. Ke-yan Wu
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Corresponding author

Correspondence to Yan-bing Ding.

Additional information

Yan-bing Ding, Bin Deng, and You-sheng Huang contributed equally to this work.

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Ding, Yb., Deng, B., Huang, Ys. et al. A High Level of Integrin α6 Expression in Human Intrahepatic Cholangiocarcinoma Cells Is Associated with a Migratory and Invasive Phenotype. Dig Dis Sci 58, 1627–1635 (2013). https://doi.org/10.1007/s10620-012-2524-6

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  • DOI: https://doi.org/10.1007/s10620-012-2524-6

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