Role and mechanism of circ-PRKCI in hepatocellular carcinoma
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摘要
BACKGROUND The circular RNA circ-PRKCI is an endogenous non-coding RNA that forms a covalently closed ring after reverse splicing, which plays a key role in the occurrence and development of multiple digestive system tumors.AIM To investigate the role and mechanism of circ-PRKCI in the occurrence and development of hepatocellular carcinoma(HCC).METHODS This study used real-time polymerase chain reaction to detect the expression of circ-PRKCI in tumor tissues, tumor adjacent tissues, and blood in patients with HCC and other digestive system tumor cells. A series of functional tests were performed to explore whether circ-PRKCI affects the growth of HCC cells and what is its mechanism in HCC. Meanwhile, fluorescence in situ hybridization was used to detect the subcellular localization of circ-PRKCI. Survival analysis was performed to predict the correlation between circ-PRKCI and the prognosis of HCC. Chi-square test and t-test were performed for statistical analyses.RESULTS The level of circ-PRKCI was significantly higher in HCC tissues than in tumor adjacent tissues, and in HCC cell lines than in cells lines of esophageal, liver,stomach, and colon cancers. A series of functional tests showed that circ-PRKCI substantially inhibited cell apoptosis and promoted cell invasion. It was foundthat circ-PRKCI can act as the sponge of miRNA-545 to reduce the expression of AKT3 protein. Moreover, the result of survival analysis showed that circ-PRKCI target gene E2 F7 can reduce liver cancer patients' survival rate. And clinical data suggested that the distribution of circ-PRKCI rose with the depth of invasion,lymph node metastasis, distant metastasis, and TNM stage, indicating that circPRKCI may affect the survival and prognosis of patients with HCC by regulating E2 E7.CONCLUSION This study explores the role and mechanism of circ-PRKCI in HCC, which provides a new research direction and theoretical basis for the treatment of HCC.
BACKGROUND The circular RNA circ-PRKCI is an endogenous non-coding RNA that forms a covalently closed ring after reverse splicing, which plays a key role in the occurrence and development of multiple digestive system tumors.AIM To investigate the role and mechanism of circ-PRKCI in the occurrence and development of hepatocellular carcinoma(HCC).METHODS This study used real-time polymerase chain reaction to detect the expression of circ-PRKCI in tumor tissues, tumor adjacent tissues, and blood in patients with HCC and other digestive system tumor cells. A series of functional tests were performed to explore whether circ-PRKCI affects the growth of HCC cells and what is its mechanism in HCC. Meanwhile, fluorescence in situ hybridization was used to detect the subcellular localization of circ-PRKCI. Survival analysis was performed to predict the correlation between circ-PRKCI and the prognosis of HCC. Chi-square test and t-test were performed for statistical analyses.RESULTS The level of circ-PRKCI was significantly higher in HCC tissues than in tumor adjacent tissues, and in HCC cell lines than in cells lines of esophageal, liver,stomach, and colon cancers. A series of functional tests showed that circ-PRKCI substantially inhibited cell apoptosis and promoted cell invasion. It was foundthat circ-PRKCI can act as the sponge of miRNA-545 to reduce the expression of AKT3 protein. Moreover, the result of survival analysis showed that circ-PRKCI target gene E2 F7 can reduce liver cancer patients' survival rate. And clinical data suggested that the distribution of circ-PRKCI rose with the depth of invasion,lymph node metastasis, distant metastasis, and TNM stage, indicating that circPRKCI may affect the survival and prognosis of patients with HCC by regulating E2 E7.CONCLUSION This study explores the role and mechanism of circ-PRKCI in HCC, which provides a new research direction and theoretical basis for the treatment of HCC.
BACKGROUND The circular RNA circ-PRKCI is an endogenous non-coding RNA that forms a covalently closed ring after reverse splicing, which plays a key role in the occurrence and development of multiple digestive system tumors.AIM To investigate the role and mechanism of circ-PRKCI in the occurrence and development of hepatocellular carcinoma(HCC).METHODS This study used real-time polymerase chain reaction to detect the expression of circ-PRKCI in tumor tissues, tumor adjacent tissues, and blood in patients with HCC and other digestive system tumor cells. A series of functional tests were performed to explore whether circ-PRKCI affects the growth of HCC cells and what is its mechanism in HCC. Meanwhile, fluorescence in situ hybridization was used to detect the subcellular localization of circ-PRKCI. Survival analysis was performed to predict the correlation between circ-PRKCI and the prognosis of HCC. Chi-square test and t-test were performed for statistical analyses.RESULTS The level of circ-PRKCI was significantly higher in HCC tissues than in tumor adjacent tissues, and in HCC cell lines than in cells lines of esophageal, liver,stomach, and colon cancers. A series of functional tests showed that circ-PRKCI substantially inhibited cell apoptosis and promoted cell invasion. It was foundthat circ-PRKCI can act as the sponge of miRNA-545 to reduce the expression of AKT3 protein. Moreover, the result of survival analysis showed that circ-PRKCI target gene E2 F7 can reduce liver cancer patients' survival rate. And clinical data suggested that the distribution of circ-PRKCI rose with the depth of invasion,lymph node metastasis, distant metastasis, and TNM stage, indicating that circPRKCI may affect the survival and prognosis of patients with HCC by regulating E2 E7.CONCLUSION This study explores the role and mechanism of circ-PRKCI in HCC, which provides a new research direction and theoretical basis for the treatment of HCC.
引文
1 Chen K,Liu XH,Wang FR,Liu HP,Huang ZP,Chen X.The prognostic value of decreased NDRG1expression in patients with digestive system cancers:A meta-analysis.Medicine(Baltimore)2018;97:e12455[PMID:30313035 DOI:10.1097/MD.0000000000012455]
2 Gong J,Lv L,Huo J.Roles of F-box proteins in human digestive system tumors(Review).Int J Oncol2014;45:2199-2207[PMID:25270675 DOI:10.3892/ijo.2014.2684]
3 Liu Y,Zhang M,Liang L,Li J,Chen YX.Over-expression of lncRNA DANCR is associated with advanced tumor progression and poor prognosis in patients with colorectal cancer.Int J Clin Exp Pathol2015;8:11480-11484[PMID:26617879]
4 Sun L,Dong S,Dong C,Sun K,Meng W,Lv P,Yin H,Ming L,He F.Predictive value of plasma miRNA-718 for esophageal squamous cell carcinoma.Cancer Biomark 2016;16:265-273[PMID:26756617 DOI:10.3233/CBM-150564]
5 YiRen H,YingCong Y,Sunwu Y,Keqin L,Xiaochun T,Senrui C,Ende C,XiZhou L,Yanfan C.Long noncoding RNA MALAT1 regulates autophagy associated chemoresistance via miR-23b-3p sequestration in gastric cancer.Mol Cancer 2017;16:174[PMID:29162158 DOI:10.1186/s12943-017-0743-3]
6 Zhang L,Huang LS,Chen G,Feng ZB.Potential Targets and Clinical Value of MiR-224-5p in Cancers of the Digestive Tract.Cell Physiol Biochem 2017;44:682-700[PMID:29169158 DOI:10.1159/000485281]
7 Xie Y,Li T,Mo X,Guo J.[Circular RNAs and their roles in tumorigenesis].Sheng Wu Gong Cheng Xue Bao 2016;32:1507-1518[PMID:29034621 DOI:10.13345/j.cjb.160122]
8 Zhou L,Li Y,Jiang W,Zhang H,Wen Z,Su Y,Wu F,Zhi Z,Shen Q,Li H,Xu X,Tang W.Downregulation of circ-PRKCI inhibits cell migration and proliferation in Hirschsprung disease by suppressing the expression of miR-1324 target PLCB1.Cell Cycle 2018;17:1092-1101[PMID:29895226 DOI:10.1080/15384101.2018.1480210]
9 Hsiao KY,Lin YC,Gupta SK,Chang N,Yen L,Sun HS,Tsai SJ.Noncoding Effects of Circular RNACCDC66 Promote Colon Cancer Growth and Metastasis.Cancer Res 2017;77:2339-2350[PMID:28249903 DOI:10.1158/0008-5472.CAN-16-1883]
10 Chen S,Li T,Zhao Q,Xiao B,Guo J.Using circular RNA hsa_circ_0000190 as a new biomarker in the diagnosis of gastric cancer.Clin Chim Acta 2017;466:167-171[PMID:28130019 DOI:10.1016/j.cca.2017.01.025]
11 Qiu M,Xia W,Chen R,Wang S,Xu Y,Ma Z,Xu W,Zhang E,Wang J,Fang T,Hu J,Dong G,Yin R,Wang J,Xu L.The Circular RNA circPRKCI Promotes Tumor Growth in Lung Adenocarcinoma.Cancer Res 2018;78:2839-2851[PMID:29588350 DOI:10.1158/0008-5472.CAN-17-2808]
12 Shi N,Shan B,Gu B,Song Y,Chu H,Qian L.Circular RNA circ-PRKCI functions as a competitive endogenous RNA to regulate AKT3 expression by sponging miR-3680-3p in esophageal squamous cell carcinoma.J Cell Biochem 2019;120:10021-10030[PMID:30659640 DOI:10.1002/jcb.28285]
13 Ng WL,Mohd Mohidin TB,Shukla K.Functional role of circular RNAs in cancer development and progression.RNA Biol 2018;15:995-1005[PMID:29954251 DOI:10.1080/15476286.2018.1486659]
14 Wu Y,Zhang Y,Zhang Y,Wang JJ.CircRNA hsa_circ_0005105 upregulates NAMPT expression and promotes chondrocyte extracellular matrix degradation by sponging miR-26a.Cell Biol Int 2017;41:1283-1289[PMID:28276108 DOI:10.1002/cbin.10761]
15 Liu L,Wang J,Khanabdali R,Kalionis B,Tai X,Xia S.Circular RNAs:Isolation,characterization and their potential role in diseases.RNA Biol 2017;14:1715-1721[PMID:28820337 DOI:10.1080/15476286.2017.1367886]
16 Salzman J,Gawad C,Wang PL,Lacayo N,Brown PO.Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types.PLoS One 2012;7:e30733[PMID:22319583 DOI:10.1371/journal.pone.0030733]
17 Chen LL.The biogenesis and emerging roles of circular RNAs.Nat Rev Mol Cell Biol 2016;17:205-211[PMID:26908011 DOI:10.1038/nrm.2015.32]
18 Chen Y,Li C,Tan C,Mai G,Liu X.[Circular RNA in human disease and their potential clinic significance].Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2017;34:133-137[PMID:28186613 DOI:10.3760/cma.j.issn.1003-9406.2017.01.031]
19 Li X,Liu CX,Xue W,Zhang Y,Jiang S,Yin QF,Wei J,Yao RW,Yang L,Chen LL.Coordinated circRNA Biogenesis and Function with NF90/NF110 in Viral Infection.Mol Cell 2017;67:214-227.e7[PMID:28625552 DOI:10.1016/j.molcel.2017.05.023]
20 Wang K,Gan TY,Li N,Liu CY,Zhou LY,Gao JN,Chen C,Yan KW,Ponnusamy M,Zhang YH,Li PF.Circular RNA mediates cardiomyocyte death via miRNA-dependent upregulation of MTP18 expression.Cell Death Differ 2017;24:1111-1120[PMID:28498369 DOI:10.1038/cdd.2017.61]
21 Agarwal E,Brattain MG,Chowdhury S.Cell survival and metastasis regulation by Akt signaling in colorectal cancer.Cell Signal 2013;25:1711-1719[PMID:23603750 DOI:10.1016/j.cellsig.2013.03.025]
22 Peng L,Chen G,Zhu Z,Shen Z,Du C,Zang R,Su Y,Xie H,Li H,Xu X,Xia Y,Tang W.Circular RNAZNF609 functions as a competitive endogenous RNA to regulate AKT3 expression by sponging miR-150-5p in Hirschsprung's disease.Oncotarget 2017;8:808-818[PMID:27903978 DOI:10.18632/oncotarget.13656]
23 Li Z,Yanfang W,Li J,Jiang P,Peng T,Chen K,Zhao X,Zhang Y,Zhen P,Zhu J,Li X.Tumor-released exosomal circular RNA PDE8A promotes invasive growth via the miR-338/MACC1/MET pathway in pancreatic cancer.Cancer Lett 2018;432:237-250[PMID:29709702 DOI:10.1016/j.canlet.2018.04.035]
24 Xu L,Zhang M,Zheng X,Yi P,Lan C,Xu M.The circular RNA ciRS-7(Cdr1as)acts as a risk factor of hepatic microvascular invasion in hepatocellular carcinoma.J Cancer Res Clin Oncol 2017;143:17-27[PMID:27614453 DOI:10.1007/s00432-016-2256-7]
25 Wang S,Cui S,Zhao W,Qian Z,Liu H,Chen Y,Lv F,Ding HG.Screening and bioinformatics analysis of circular RNA expression profiles in hepatitis B-related hepatocellular carcinoma.Cancer Biomark 2018;22:631-640[PMID:29914004 DOI:10.3233/CBM-170910]
2 Gong J,Lv L,Huo J.Roles of F-box proteins in human digestive system tumors(Review).Int J Oncol2014;45:2199-2207[PMID:25270675 DOI:10.3892/ijo.2014.2684]
3 Liu Y,Zhang M,Liang L,Li J,Chen YX.Over-expression of lncRNA DANCR is associated with advanced tumor progression and poor prognosis in patients with colorectal cancer.Int J Clin Exp Pathol2015;8:11480-11484[PMID:26617879]
4 Sun L,Dong S,Dong C,Sun K,Meng W,Lv P,Yin H,Ming L,He F.Predictive value of plasma miRNA-718 for esophageal squamous cell carcinoma.Cancer Biomark 2016;16:265-273[PMID:26756617 DOI:10.3233/CBM-150564]
5 YiRen H,YingCong Y,Sunwu Y,Keqin L,Xiaochun T,Senrui C,Ende C,XiZhou L,Yanfan C.Long noncoding RNA MALAT1 regulates autophagy associated chemoresistance via miR-23b-3p sequestration in gastric cancer.Mol Cancer 2017;16:174[PMID:29162158 DOI:10.1186/s12943-017-0743-3]
6 Zhang L,Huang LS,Chen G,Feng ZB.Potential Targets and Clinical Value of MiR-224-5p in Cancers of the Digestive Tract.Cell Physiol Biochem 2017;44:682-700[PMID:29169158 DOI:10.1159/000485281]
7 Xie Y,Li T,Mo X,Guo J.[Circular RNAs and their roles in tumorigenesis].Sheng Wu Gong Cheng Xue Bao 2016;32:1507-1518[PMID:29034621 DOI:10.13345/j.cjb.160122]
8 Zhou L,Li Y,Jiang W,Zhang H,Wen Z,Su Y,Wu F,Zhi Z,Shen Q,Li H,Xu X,Tang W.Downregulation of circ-PRKCI inhibits cell migration and proliferation in Hirschsprung disease by suppressing the expression of miR-1324 target PLCB1.Cell Cycle 2018;17:1092-1101[PMID:29895226 DOI:10.1080/15384101.2018.1480210]
9 Hsiao KY,Lin YC,Gupta SK,Chang N,Yen L,Sun HS,Tsai SJ.Noncoding Effects of Circular RNACCDC66 Promote Colon Cancer Growth and Metastasis.Cancer Res 2017;77:2339-2350[PMID:28249903 DOI:10.1158/0008-5472.CAN-16-1883]
10 Chen S,Li T,Zhao Q,Xiao B,Guo J.Using circular RNA hsa_circ_0000190 as a new biomarker in the diagnosis of gastric cancer.Clin Chim Acta 2017;466:167-171[PMID:28130019 DOI:10.1016/j.cca.2017.01.025]
11 Qiu M,Xia W,Chen R,Wang S,Xu Y,Ma Z,Xu W,Zhang E,Wang J,Fang T,Hu J,Dong G,Yin R,Wang J,Xu L.The Circular RNA circPRKCI Promotes Tumor Growth in Lung Adenocarcinoma.Cancer Res 2018;78:2839-2851[PMID:29588350 DOI:10.1158/0008-5472.CAN-17-2808]
12 Shi N,Shan B,Gu B,Song Y,Chu H,Qian L.Circular RNA circ-PRKCI functions as a competitive endogenous RNA to regulate AKT3 expression by sponging miR-3680-3p in esophageal squamous cell carcinoma.J Cell Biochem 2019;120:10021-10030[PMID:30659640 DOI:10.1002/jcb.28285]
13 Ng WL,Mohd Mohidin TB,Shukla K.Functional role of circular RNAs in cancer development and progression.RNA Biol 2018;15:995-1005[PMID:29954251 DOI:10.1080/15476286.2018.1486659]
14 Wu Y,Zhang Y,Zhang Y,Wang JJ.CircRNA hsa_circ_0005105 upregulates NAMPT expression and promotes chondrocyte extracellular matrix degradation by sponging miR-26a.Cell Biol Int 2017;41:1283-1289[PMID:28276108 DOI:10.1002/cbin.10761]
15 Liu L,Wang J,Khanabdali R,Kalionis B,Tai X,Xia S.Circular RNAs:Isolation,characterization and their potential role in diseases.RNA Biol 2017;14:1715-1721[PMID:28820337 DOI:10.1080/15476286.2017.1367886]
16 Salzman J,Gawad C,Wang PL,Lacayo N,Brown PO.Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types.PLoS One 2012;7:e30733[PMID:22319583 DOI:10.1371/journal.pone.0030733]
17 Chen LL.The biogenesis and emerging roles of circular RNAs.Nat Rev Mol Cell Biol 2016;17:205-211[PMID:26908011 DOI:10.1038/nrm.2015.32]
18 Chen Y,Li C,Tan C,Mai G,Liu X.[Circular RNA in human disease and their potential clinic significance].Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2017;34:133-137[PMID:28186613 DOI:10.3760/cma.j.issn.1003-9406.2017.01.031]
19 Li X,Liu CX,Xue W,Zhang Y,Jiang S,Yin QF,Wei J,Yao RW,Yang L,Chen LL.Coordinated circRNA Biogenesis and Function with NF90/NF110 in Viral Infection.Mol Cell 2017;67:214-227.e7[PMID:28625552 DOI:10.1016/j.molcel.2017.05.023]
20 Wang K,Gan TY,Li N,Liu CY,Zhou LY,Gao JN,Chen C,Yan KW,Ponnusamy M,Zhang YH,Li PF.Circular RNA mediates cardiomyocyte death via miRNA-dependent upregulation of MTP18 expression.Cell Death Differ 2017;24:1111-1120[PMID:28498369 DOI:10.1038/cdd.2017.61]
21 Agarwal E,Brattain MG,Chowdhury S.Cell survival and metastasis regulation by Akt signaling in colorectal cancer.Cell Signal 2013;25:1711-1719[PMID:23603750 DOI:10.1016/j.cellsig.2013.03.025]
22 Peng L,Chen G,Zhu Z,Shen Z,Du C,Zang R,Su Y,Xie H,Li H,Xu X,Xia Y,Tang W.Circular RNAZNF609 functions as a competitive endogenous RNA to regulate AKT3 expression by sponging miR-150-5p in Hirschsprung's disease.Oncotarget 2017;8:808-818[PMID:27903978 DOI:10.18632/oncotarget.13656]
23 Li Z,Yanfang W,Li J,Jiang P,Peng T,Chen K,Zhao X,Zhang Y,Zhen P,Zhu J,Li X.Tumor-released exosomal circular RNA PDE8A promotes invasive growth via the miR-338/MACC1/MET pathway in pancreatic cancer.Cancer Lett 2018;432:237-250[PMID:29709702 DOI:10.1016/j.canlet.2018.04.035]
24 Xu L,Zhang M,Zheng X,Yi P,Lan C,Xu M.The circular RNA ciRS-7(Cdr1as)acts as a risk factor of hepatic microvascular invasion in hepatocellular carcinoma.J Cancer Res Clin Oncol 2017;143:17-27[PMID:27614453 DOI:10.1007/s00432-016-2256-7]
25 Wang S,Cui S,Zhao W,Qian Z,Liu H,Chen Y,Lv F,Ding HG.Screening and bioinformatics analysis of circular RNA expression profiles in hepatitis B-related hepatocellular carcinoma.Cancer Biomark 2018;22:631-640[PMID:29914004 DOI:10.3233/CBM-170910]