Peptidylarginine deiminase IV promotes the development of chemoresistance through inducing autophagy in hepatocellular carcinoma.
BACKGROUND
Peptidylarginine deiminase IV (PADI4) is widely distributed in several tissues and the expression is correlated with many pathological processes. Chemotherapy remains a major treatment alternatively to surgery for a large number of patients at the advanced stage of hepatocellular carcinoma (HCC). However, the role of PADI4 in the chemoresistance of HCC has not been identified.


METHODS
MTT and PI/Annexin V assay were employed to examine the proliferation and apoptosis of HCC cell lines. The expression of MDR1 is detected by Realtime PCR. GFP tagged LC3 expression vector and electron microscopy are utilized to demonstrate the occurrence of autophagy.


RESULTS
We observed that the elevated PADI4 expression is associated with chemoresistance in HCC patients with TACE after surgery. In addition, we found that overexpression of PADI4 in HCC cell lines lead to the resistance to chemotherapeutic agents in vitro and in vivo. Interestingly, the HCC cells that overexpressed PADI4 were observed to undergo autophagy which was known as a protective mechanism for cells to resist the cell tosicity from chemotherapy. Autophagy inhibitor could effectively restore the sensitivity of HCC cells to chemotherapy in vitro and in vivo.


CONCLUSIONS
These results indicate that PADI4 may induce chemoresistance in HCC cells by leading autophagy.
Department of Clinical Laboratory, Shanghai East Hospital, Tongji University Medical School, No. 150, Jimo Road, Shanghai, 200120 China.
Tingting
T
Fan
Clinical Oncology Laboratory, Changzhou cancer Hospital of Soochow University, Changzhou, 213001 China ; Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438 China.
Changsong
C
Zhang
Department of Clinical Laboratory, Shanghai East Hospital, Tongji University Medical School, No. 150, Jimo Road, Shanghai, 200120 China.
Ming
M
Zong
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438 China.
Qiudong
Q
Zhao
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438 China.
Xue
X
Yang
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438 China.
Chong
C
Hao
Department of Clinical Laboratory, Shanghai East Hospital, Tongji University Medical School, No. 150, Jimo Road, Shanghai, 200120 China.
Hui
H
Zhang
Department of Clinical Laboratory, Shanghai East Hospital, Tongji University Medical School, No. 150, Jimo Road, Shanghai, 200120 China.
Shanshan
S
Yu
Department of Clinical Laboratory, Shanghai East Hospital, Tongji University Medical School, No. 150, Jimo Road, Shanghai, 200120 China.
Jinhu
J
Guo
Department of Clinical Laboratory, Shanghai East Hospital, Tongji University Medical School, No. 150, Jimo Road, Shanghai, 200120 China.
Ruhan
R
Gong
Department of Clinical Laboratory, Shanghai East Hospital, Tongji University Medical School, No. 150, Jimo Road, Shanghai, 200120 China.
Shasha
S
Fan
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438 China.
Lixin
L
Wei
Department of Clinical Laboratory, Shanghai East Hospital, Tongji University Medical School, No. 150, Jimo Road, Shanghai, 200120 China.
Lieying
L
Fan
Autophagy; Chemoresistance; Hepatocellular Carcinoma; PADI4