Skip to main content
Top
Published in: Digestive Diseases and Sciences 2/2020

01-02-2020 | Computed Tomography | Original Article

LRRK2 Is Associated with Recurrence-Free Survival in Intrahepatic Cholangiocarcinoma and Downregulation of LRRK2 Suppresses Tumor Progress In Vitro

Authors: Shen Gu, Jun Chen, Qun Zhou, Minghao Yan, Jian He, Xiaodong Han, Yudong Qiu

Published in: Digestive Diseases and Sciences | Issue 2/2020

Login to get access

Abstract

Background

The leucine-rich repeat kinase 2 (LRRK2) gene was confirmed to be associated with a variety of diseases, while the physiological function of LRRK2 remains poorly understood. Intrahepatic cholangiocarcinoma (ICC) has over the last 10 years become the focus of increasing concern largely. Despite recent progress in the standard of care and management options for ICC, the prognosis for this devastating cancer remains dismal.

Methods

A total of 57 consecutive ICC patients who underwent curative hepatectomy in our institution were included in our study. We conduct a retrospective study to evaluate the prognostic value of LRRK2 in ICC after resection. The mechanism of LRRK2 in ICC development was also investigated in vitro.

Results

All patients were divided into two groups according to the content of LRRK2 in the tissue microarray blocks via immunohistochemistry: low-LRRK2 group (n = 33) and high-LRRK2 group (n = 24). The recurrence-free survival rate of high-LRRK2 group was significantly poorer than that of low-LRRK2 group (P = 0.010). Multivariate analysis showed high-LRRK2 was the prognostic factor for recurrence-free survival after hepatectomy. We demonstrated that downregulation of LRRK2 depressed the proliferation and metastasis of ICC cells in vitro.

Conclusion

We provide evidence that LRRK2 was an independent prognostic factor for ICC in humans by participating in the proliferation and metastasis of ICC cells.
Appendix
Available only for authorised users
Literature
1.
go back to reference Maithel SK, Gamblin TC, Kamel I, Corona-Villalobos CP, Thomas M, Pawlik TM. Multidisciplinary approaches to intrahepatic cholangiocarcinoma. Cancer. 2013;119:3929–3942.CrossRef Maithel SK, Gamblin TC, Kamel I, Corona-Villalobos CP, Thomas M, Pawlik TM. Multidisciplinary approaches to intrahepatic cholangiocarcinoma. Cancer. 2013;119:3929–3942.CrossRef
2.
go back to reference Sirica AE, Gores GJ, Groopman JD, et al. Intrahepatic cholangiocarcinoma: continuing challenges and translational advances. Hepatology. 2018;69(4):1803–1815.CrossRef Sirica AE, Gores GJ, Groopman JD, et al. Intrahepatic cholangiocarcinoma: continuing challenges and translational advances. Hepatology. 2018;69(4):1803–1815.CrossRef
3.
go back to reference Zhang CH, Xu H, Zhou ZP, et al. Blocking of the EGFR-STAT3 signaling pathway through afatinib treatment inhibited the intrahepatic cholangiocarcinoma. Exp Ther Med. 2018;15:4995–5000.PubMedPubMedCentral Zhang CH, Xu H, Zhou ZP, et al. Blocking of the EGFR-STAT3 signaling pathway through afatinib treatment inhibited the intrahepatic cholangiocarcinoma. Exp Ther Med. 2018;15:4995–5000.PubMedPubMedCentral
4.
go back to reference Patel T. New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma. J Gastroenterol. 2014;49:165–172.CrossRef Patel T. New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma. J Gastroenterol. 2014;49:165–172.CrossRef
5.
go back to reference Nakanuma Y, Harada K, Ishikawa A, Zen Y, Sasaki M. Anatomic and molecular pathology of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg. 2003;10:265–281.CrossRef Nakanuma Y, Harada K, Ishikawa A, Zen Y, Sasaki M. Anatomic and molecular pathology of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg. 2003;10:265–281.CrossRef
6.
go back to reference Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant Parkinsonism with pleomorphic pathology. Neuron. 2004;44:601–607.CrossRef Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant Parkinsonism with pleomorphic pathology. Neuron. 2004;44:601–607.CrossRef
7.
go back to reference Cookson MR. LRRK2 pathways leading to neurodegeneration. Curr Neurol Neurosci. 2015;15:42.CrossRef Cookson MR. LRRK2 pathways leading to neurodegeneration. Curr Neurol Neurosci. 2015;15:42.CrossRef
8.
go back to reference Moehle MS, Webber PJ, Tse T, et al. LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci. 2012;32:1602–1611.CrossRef Moehle MS, Webber PJ, Tse T, et al. LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci. 2012;32:1602–1611.CrossRef
9.
go back to reference Schapansky J, Nardozzi JD, LaVoie MJ. The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson’s disease. Neuroscience. 2015;302:74–88.CrossRef Schapansky J, Nardozzi JD, LaVoie MJ. The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson’s disease. Neuroscience. 2015;302:74–88.CrossRef
10.
go back to reference Inzelberg R, Cohen OS, Aharon-Peretz J, et al. The LRRK2 G2019S mutation is associated with Parkinson disease and concomitant non-skin cancers. Neurology. 2012;78:781–786.CrossRef Inzelberg R, Cohen OS, Aharon-Peretz J, et al. The LRRK2 G2019S mutation is associated with Parkinson disease and concomitant non-skin cancers. Neurology. 2012;78:781–786.CrossRef
11.
go back to reference Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40:955–962.CrossRef Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40:955–962.CrossRef
12.
go back to reference Looyenga BD, Furge KA, Dykema KJ, et al. Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas. Proc Natl Acad Sci USA. 2011;108:1439–1444.CrossRef Looyenga BD, Furge KA, Dykema KJ, et al. Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas. Proc Natl Acad Sci USA. 2011;108:1439–1444.CrossRef
13.
go back to reference Waro BJ, Aasly JO. Exploring cancer in LRRK2 mutation carriers and idiopathic Parkinson’s disease. Brain Behav. 2018;8:e00858.CrossRef Waro BJ, Aasly JO. Exploring cancer in LRRK2 mutation carriers and idiopathic Parkinson’s disease. Brain Behav. 2018;8:e00858.CrossRef
14.
go back to reference Sierra M, Martinez-Rodriguez I, Sanchez-Juan P, et al. Prospective clinical and DaT-SPECT imaging in premotor LRRK2 G2019S-associated Parkinson disease. Neurology. 2017;89:439–444.CrossRef Sierra M, Martinez-Rodriguez I, Sanchez-Juan P, et al. Prospective clinical and DaT-SPECT imaging in premotor LRRK2 G2019S-associated Parkinson disease. Neurology. 2017;89:439–444.CrossRef
15.
go back to reference Vilas D, Ispierto L, Alvarez R, et al. Clinical and imaging markers in premotor LRRK2 G2019S mutation carriers. Parkinsonism Relat Disord. 2015;21:1170–1176.CrossRef Vilas D, Ispierto L, Alvarez R, et al. Clinical and imaging markers in premotor LRRK2 G2019S mutation carriers. Parkinsonism Relat Disord. 2015;21:1170–1176.CrossRef
16.
go back to reference Park HJ, Jang KM, Kang TW, et al. Identification of imaging predictors discriminating different primary liver tumours in patients with chronic liver disease on Gadoxetic acid-enhanced MRI: a classification tree analysis. Eur Radiol. 2016;26:3102–3111.CrossRef Park HJ, Jang KM, Kang TW, et al. Identification of imaging predictors discriminating different primary liver tumours in patients with chronic liver disease on Gadoxetic acid-enhanced MRI: a classification tree analysis. Eur Radiol. 2016;26:3102–3111.CrossRef
17.
go back to reference Tsunematsu S, Chuma M, Kamiyama T, et al. Intratumoral artery on contrast-enhanced computed tomography imaging: differentiating intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma. Abdom Imaging. 2015;40:1492–1499.CrossRef Tsunematsu S, Chuma M, Kamiyama T, et al. Intratumoral artery on contrast-enhanced computed tomography imaging: differentiating intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma. Abdom Imaging. 2015;40:1492–1499.CrossRef
18.
go back to reference Fujita N, Asayama Y, Nishie A, et al. Mass-forming intrahepatic cholangiocarcinoma: Enhancement patterns in the arterial phase of dynamic hepatic CT—correlation with clinicopathological findings. Eur Radiol. 2017;27:498–506.CrossRef Fujita N, Asayama Y, Nishie A, et al. Mass-forming intrahepatic cholangiocarcinoma: Enhancement patterns in the arterial phase of dynamic hepatic CT—correlation with clinicopathological findings. Eur Radiol. 2017;27:498–506.CrossRef
19.
go back to reference Wang C, Dai J, Sun Z, et al. Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process. Exp Cell Res. 2015;331:115–122.CrossRef Wang C, Dai J, Sun Z, et al. Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process. Exp Cell Res. 2015;331:115–122.CrossRef
20.
go back to reference Zhu Y, Chen J, Kong WW, et al. Predicting IDH mutation status of intrahepatic cholangiocarcinomas based on contrast-enhanced CT features. Eur Radiol. 2018;28:159–169.CrossRef Zhu Y, Chen J, Kong WW, et al. Predicting IDH mutation status of intrahepatic cholangiocarcinomas based on contrast-enhanced CT features. Eur Radiol. 2018;28:159–169.CrossRef
21.
go back to reference Shuang Z, Mao Y, Lin G, et al. Alpha-L-fucosidase serves as a prognostic indicator for intrahepatic cholangiocarcinoma and inhibits its invasion capacity. Biomed Res Int. 2018;2018:8182575.CrossRef Shuang Z, Mao Y, Lin G, et al. Alpha-L-fucosidase serves as a prognostic indicator for intrahepatic cholangiocarcinoma and inhibits its invasion capacity. Biomed Res Int. 2018;2018:8182575.CrossRef
22.
go back to reference Sirica AE. The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma. Nat Rev Gastroenterol Hepatol. 2011;9:44–54.CrossRef Sirica AE. The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma. Nat Rev Gastroenterol Hepatol. 2011;9:44–54.CrossRef
23.
go back to reference Thanee M, Loilome W, Techasen A, et al. Quantitative changes in tumor-associated M2 macrophages characterize cholangiocarcinoma and their association with metastasis. Asian Pac J Cancer Prev. 2015;16:3043–3050.CrossRef Thanee M, Loilome W, Techasen A, et al. Quantitative changes in tumor-associated M2 macrophages characterize cholangiocarcinoma and their association with metastasis. Asian Pac J Cancer Prev. 2015;16:3043–3050.CrossRef
24.
go back to reference Gardet A, Benita Y, Li C, et al. LRRK2 is involved in the IFN-gamma response and host response to pathogens. J Immunol. 2010;185:5577–5585.CrossRef Gardet A, Benita Y, Li C, et al. LRRK2 is involved in the IFN-gamma response and host response to pathogens. J Immunol. 2010;185:5577–5585.CrossRef
25.
go back to reference Pons B, Armengol G, Livingstone M, et al. Association between LRRK2 and 4E-BP1 protein levels in normal and malignant cells. Oncol Rep. 2012;27:225–231.PubMed Pons B, Armengol G, Livingstone M, et al. Association between LRRK2 and 4E-BP1 protein levels in normal and malignant cells. Oncol Rep. 2012;27:225–231.PubMed
26.
go back to reference Chan SL, Tan EK. Targeting LRRK2 in Parkinson’s disease: an update on recent developments. Expert Opin Ther Targets. 2017;21:601–610.CrossRef Chan SL, Tan EK. Targeting LRRK2 in Parkinson’s disease: an update on recent developments. Expert Opin Ther Targets. 2017;21:601–610.CrossRef
27.
go back to reference Henderson JL, Kormos BL, Hayward MM, et al. Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor. J Med Chem. 2015;58:419–432.CrossRef Henderson JL, Kormos BL, Hayward MM, et al. Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor. J Med Chem. 2015;58:419–432.CrossRef
Metadata
Title
LRRK2 Is Associated with Recurrence-Free Survival in Intrahepatic Cholangiocarcinoma and Downregulation of LRRK2 Suppresses Tumor Progress In Vitro
Authors
Shen Gu
Jun Chen
Qun Zhou
Minghao Yan
Jian He
Xiaodong Han
Yudong Qiu
Publication date
01-02-2020
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 2/2020
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-019-05806-0

Other articles of this Issue 2/2020

Digestive Diseases and Sciences 2/2020 Go to the issue