TY - JOUR
T1 - Autophagy-related gene LC3 expression in tumor and liver microenvironments significantly predicts recurrence of hepatocellular carcinoma after surgical resection article
AU - Lin, Chih Wen
AU - Chen, Yaw Sen
AU - Lin, Chih Che
AU - Lee, Po Huang
AU - Lo, Gin Ho
AU - Hsu, Chia Chang
AU - Hsieh, Pei Min
AU - Koh, Kah Wee
AU - Chou, Tsung Ching
AU - Dai, Chia Yen
AU - Huang, Jee Fu
AU - Chuang, Wan Long
AU - Chen, Yao Li
AU - Yu, Ming Lung
N1 - Funding Information:
We thank Yu-Chan Li, Bao-Sheng Hou, and Shuting Lin for the collection and analysis of data. This work was financially and partly supported by the "Center for Intelligent Drug Systems and Smart Bio-devices" from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education in Taiwan. We also thank Liver Disease Prevention and Treatment Research Foundation, Taiwan for part financial support.
Funding Information:
Guarantor of the article: Ming-Lung Yu. Specific author contributions: Lin C.W. performed the experiments, collected the patient information and data, analyzed the data, and wrote the manuscript together with Chen Y.S., Lin C.C., Lee P.H., Lo G.H., Hsu C.C., Hsieh P.M., Koh K. W., Chou T.C., Dai C.Y., Huang J.F., Chuang W.L., and Chen Y.L. Yu M.L. designed the study and wrote the manuscript together with Lin C.W. All of the authors made important suggestions to the manuscript and had reviewed and approved the final version of the manuscript, including the authorship list. Financial support: This study was supported by grants from MOST 103-2314-B-037-061-MY3, MOST 103-2314-B-650-005-MY2, MOST 105-2314-B-037-062-MY2, MOST 105-2314-B-650-004-MY3, and MOST 106-2314-B-037-074, E-Da Hospital (EDAHP106036, EDAHP106048, EDAHP106054, EDAHP107040, EDAHP107041, and EDAHP107064), Kaohsiung Medical University (107CM-KMU-06 and KMU-DK107004) and Kaohsiung Medical University Hospital (MOHW 107-TDU-B-212-123006). Potential competing interests: None.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/6/1
Y1 - 2018/6/1
N2 - Background: The role of autophagy-related markers as the prognostic factor of post-operative hepatocellular carcinoma (HCC) recurrence remained controversial. Methods: Overall, 535 consecutive HCC patients undergoing curative resection from 2010 to 2014 were followed and classified with early (ER, <2 years) or late recurrence (LR). Autophagy-related markers, LC3, Beclin-1, and p62 expression was immunohistochemically assessed in HCC and adjacent non-tumor (ANT) tissues. Results: HCC recurred in 245 patients: 116 with ER and 129 with LR. The cumulative incidence of recurrence at 1, 3, 5, and 7 years was 9.7%, 33.9%, 53.3%, and 66.3%, respectively. In multivariate analysis, HCC recurrence was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (hazard ratio/95% confidence interval: 6.12/2.473-17.53, 4.18/1.285-13.61, and 1.89/1.299-2.757) and macrovascular invasion (1.63/1.043-2.492) and cirrhosis (1.59/1.088-2.326). ER was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (6.54/2.934-15.81, 3.26/1.034-10.27, and 2.09/1.313-3.321) and macrovascular and microvascular invasion (2.65/1.306-5.343 and 2.55/1.177-5.504). LR was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (5.02/1.372-18.83, 3.19/1.13-12.09, and 1.66/1.051-2.620) and cirrhosis (1.66/1.049-2.631). Patients with low and high LC3 expression in tumor and ANT tissues showed a 5-year cumulative recurrence of 94.3% and 41.7%, respectively (p < 0.001). Conclusions: The high LC3 expression in the tumor and liver microenvironments is significantly associated with lower HCC recurrence. Furthermore, tumor characteristics and liver microenvironment were also significantly associated with ER and LR, respectively. Translational impact: The analysis for LC3 expression in both the HCC and ANT tissues could identify patients at risk of HCC recurrence.
AB - Background: The role of autophagy-related markers as the prognostic factor of post-operative hepatocellular carcinoma (HCC) recurrence remained controversial. Methods: Overall, 535 consecutive HCC patients undergoing curative resection from 2010 to 2014 were followed and classified with early (ER, <2 years) or late recurrence (LR). Autophagy-related markers, LC3, Beclin-1, and p62 expression was immunohistochemically assessed in HCC and adjacent non-tumor (ANT) tissues. Results: HCC recurred in 245 patients: 116 with ER and 129 with LR. The cumulative incidence of recurrence at 1, 3, 5, and 7 years was 9.7%, 33.9%, 53.3%, and 66.3%, respectively. In multivariate analysis, HCC recurrence was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (hazard ratio/95% confidence interval: 6.12/2.473-17.53, 4.18/1.285-13.61, and 1.89/1.299-2.757) and macrovascular invasion (1.63/1.043-2.492) and cirrhosis (1.59/1.088-2.326). ER was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (6.54/2.934-15.81, 3.26/1.034-10.27, and 2.09/1.313-3.321) and macrovascular and microvascular invasion (2.65/1.306-5.343 and 2.55/1.177-5.504). LR was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (5.02/1.372-18.83, 3.19/1.13-12.09, and 1.66/1.051-2.620) and cirrhosis (1.66/1.049-2.631). Patients with low and high LC3 expression in tumor and ANT tissues showed a 5-year cumulative recurrence of 94.3% and 41.7%, respectively (p < 0.001). Conclusions: The high LC3 expression in the tumor and liver microenvironments is significantly associated with lower HCC recurrence. Furthermore, tumor characteristics and liver microenvironment were also significantly associated with ER and LR, respectively. Translational impact: The analysis for LC3 expression in both the HCC and ANT tissues could identify patients at risk of HCC recurrence.
UR - http://www.scopus.com/inward/record.url?scp=85049367890&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049367890&partnerID=8YFLogxK
U2 - 10.1038/s41424-018-0033-4
DO - 10.1038/s41424-018-0033-4
M3 - Article
C2 - 29961754
AN - SCOPUS:85049367890
SN - 2155-384X
VL - 9
JO - Clinical and Translational Gastroenterology
JF - Clinical and Translational Gastroenterology
IS - 6
M1 - 166
ER -