宫颈癌的发病机制、药物治疗及新治疗策略
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摘要
宫颈癌是妇科常见的恶性肿瘤之一,通常是由于持续感染了人乳头瘤病毒(HPV)引起。目前临床使用的治疗药物主要有传统化疗药物及靶向药物,但这两类药物均不能解决耐药性及副作用较大的问题。因此,宫颈癌新的药物治疗策略成为研究热点。本文对宫颈癌的发病机制、临床药物治疗方案及新手段做出综述,为临床治疗宫颈癌提供新的思路。
Cervical cancer is a malignant tumor caused by persistent infection with human papillomavirus(HPV). High-risk HPV can be detected in more than 70 % of cervical cancer patients. At present, the clinically applied therapeutic drugs are mainly divided into traditional chemotherapeutic drugs represented by cisplatin and targeted therapeutic drugs such as bevacizumab, but they could not solve the problems of drug resistance and side effects. Therefore, the search for new drug treatment strategies against cervical cancer has become a research hotspot. This article reviews the pathogenesis of cervical cancer, clinical drug treatment programs and new methods of drug treatment against cervical cancer, providing new ideas for clinical treatment of cervical cancer.
Cervical cancer is a malignant tumor caused by persistent infection with human papillomavirus(HPV). High-risk HPV can be detected in more than 70 % of cervical cancer patients. At present, the clinically applied therapeutic drugs are mainly divided into traditional chemotherapeutic drugs represented by cisplatin and targeted therapeutic drugs such as bevacizumab, but they could not solve the problems of drug resistance and side effects. Therefore, the search for new drug treatment strategies against cervical cancer has become a research hotspot. This article reviews the pathogenesis of cervical cancer, clinical drug treatment programs and new methods of drug treatment against cervical cancer, providing new ideas for clinical treatment of cervical cancer.
引文
[1]Berman T A,Cchiller J T.Human papillomavirus in cervical cancer and oropharyngeal cancer:one cause,two diseases[J].Cancer,2017,123(12):2219-2229.
[2]Johansson C,Schwartz S.Regulation of human papillomavirus gene expression by splicing and polyadenylation[J].Nat Rev Microbiol,2013,11(4):239-251.
[3]AltamuraG,Power K,Martano M,et al.Felis catus papillomavirus type-2 E6 binds to E6AP,promotes E6AP/p53 binding and enhances p53 proteasomal degradation[J].Sci Rep,2018,8(1):17529-17539.
[4]Chen J.Signaling pathways in HPV-associated cancers and therapeutic implications[J].Rev Med Virol,2015,25(Suppl 1):24-53.
[5]Deshpande R,Mansara P,Kaul-Ghanekar R.Alpha-linolenic acid regulates Cox2/Vegf/Map kinase pathway and decreases the expression of HPV oncoproteins E6/E7 through restoration of p53and Rb expression in human cervical cancer cell lines[J].Tumour Biol,2015,37(3):3295-3305.
[6]Poirson J,Biquand E,Straub M L,et al.Mapping the interactome of Hpv E6 and E7 oncoproteins with the ubiquitin-proteasome system[J].FEBS J,2017,284(19):3171-3201.
[7]Chen J,Zhao K N,Li R,et al.Activation of PI3K/Akt/mTORpathway and dual inhibitors of PI3K and mTOR in endometrial cancer[J].Curr Med Chem,2014,21(26):3070-3080.
[8]Spangle J M,Munger K.The HPV16 E6 oncoprotein causes prolonged receptor protein tyrosine kinase signaling and enhances internalization of phosphorylated receptor species[J].PLoSPathog,2013,9(3):1003237-1003248.
[9]Contreras-Paredes A,De La Cruz-Hern Ndez E,MartNez-RamRez I,et al.E6 variants of human papillomavirus 18 differentially modulate the protein kinase B/phosphatidylinositol 3-kinase(AKT/PI3K)signaling pathway[J].Virology,2009,383(1):78-85.
[10]Liu X,Dakic A,Zhang Y,et al.HPV E6 protein interacts physically and functionally with the cellular telomerase complex[J].Proc Natl Acad Sci USA,2009,106(44):18780-18785.
[11]Katzenellenbogen R.Telomerase induction in HPV infection and oncogenesis[J].Viruses,2017,9(7):180-191.
[12]Songyang Z,Fanning A S,Fu C,et al.Recognition of unique carboxyl-terminal motifs by distinct PDZ domains[J].Science,1997,275(5296):73-77.
[13]James C,Roberts S.Viral interactions with PDZ domaincontaining proteins-an oncogenic trait?[J].Pathogens,2016,5(1):8-29.
[14]Thomas M,Myers M P,Massimi P,et al.Analysis of multiple HPV E6 PDZ iInteractions defines type-specific PDZ fingerprints that predict oncogenic potential[J].PLoS Pathog,2016,12(8):1005766-1005786.
[15]Choi M,Lee S,Choi T,et al.Roles of the PDZ domainbinding motif of the human papillomavirus type 16 E6 on the immortalization and differentiation of primary human foreskin keratinocytes[J].Virus Genes,2014,48(2):224-232.
[16]Fan Y,Wang L,Han X,et al.Rab25 is responsible for phosphoinositide 3-kinase/AKT-mediated cisplatin resistance in human epithelial ovarian cancer cells[J].Mol Med Rep,2015,11(3):2173-2178.
[17]Bauman J E,Grandis J R.Targeting secondary immune responses to cetuximab:CD137 and the outside story[J].J Clin Invest,2014,124(6):2371-2375.
[18]Corry J,Bressel M,Fua T,et al.Prospective study of cetuximab,carboplatin,and radiation therapy for patients with locally advanced head and neck squamous cell cancer unfit for cisplatin[J].Int J Radiat Oncol Biol Phys,2017,98(17):948-954.
[19]Abdel-Rahman O.Targeting vascular endothelial growth factor(VEGF)pathway in gastric cancer:preclinical and clinical aspects[J].Crit Rev Oncol Hemat,2015,93(1):18-27.
[20]Monk B J,Sill M W,Burger R A,et al.Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix:a gynecologic oncology group study[J].J Clin Oncol,2009,27(7):1069-1074.
[21]Munagala R,Aqil F,Jeyabalan J,et al.Tanshinone IIA inhibits viral oncogene expression leading to apoptosis and inhibition of cervical cancer[J].Cancer Lett,2015,356(2 Pt B):536-546.
[22]Javadi H,Lotfi A S,Hosseinkhani S,et al.The combinational effect of E6/E7 siRNA and anti-miR-182 on apoptosis induction in HPV16-positive cervical cells[J].Artif Cells Nanomed Biotechnol,2018,6(6):1-10.
[23]Jing K,Shin S,Jeong S,et al.Docosahexaenoic acid induces the degradation of HPV E6/E7 oncoproteins by activating the ubiquitin-proteasome system[J].Cell Death Dis,2014,5(3):1524-1534.
[24]Zhang W,Che Q,Tan H,et al.Marine Streptomyces sp.derived antimycin analogues suppress HeLa cells via depletion HPV E6/E7 mediated by ROS-dependent ubiquitin-proteasome system[J].Sci Rep,2017,7(8):42180-42193.
[25]Network C G A.Comprehensive genomic characterization of head and neck squamous cell carcinomas[J].Nature,2015,517(7536):576-582.
[26]Brand T,Hartmann S,Bhola N,et al.Cross-talk signaling between HER3 and HPV16 E6 and E7 mediates resistance to PI3Kinhibitors in head and neck cancer[J].Cancer Res,2018,78(9):2383-2395.
[27]Mittal S,Banks L.Molecular mechanisms underlying human papillomavirus E6 and E7 oncoprotein-induced cell transformation[J].Mutat Res Rev Mutat Res,2017,772(16):23-35.
[28]Rastogi N,Duggal S,Singh S K,et al.Proteasome inhibition mediates p53 reactivation and anti-cancer activity of 6-Gingerol in cervical cancer cells[J].Oncotarget,2015,6(41):43310-43325.
[29]Petrone L,Ammendolia M G,Cesolini A,et al.Recombinant HPV16 E7 assembled into particles induces an immune response and specific tumour protection administered without adjuvant in an animal model[J].J Transl Med,2011,9(18):69-77.
[30]Mohit E,Bolhassani A,Zahedifard F,et al.The contribution of NT-gp96 as an adjuvant for increasing HPV16 E7-specific immunity in C57BL/6 mouse model[J].Scand J Immunol,2012,75(1):27-37.
[2]Johansson C,Schwartz S.Regulation of human papillomavirus gene expression by splicing and polyadenylation[J].Nat Rev Microbiol,2013,11(4):239-251.
[3]AltamuraG,Power K,Martano M,et al.Felis catus papillomavirus type-2 E6 binds to E6AP,promotes E6AP/p53 binding and enhances p53 proteasomal degradation[J].Sci Rep,2018,8(1):17529-17539.
[4]Chen J.Signaling pathways in HPV-associated cancers and therapeutic implications[J].Rev Med Virol,2015,25(Suppl 1):24-53.
[5]Deshpande R,Mansara P,Kaul-Ghanekar R.Alpha-linolenic acid regulates Cox2/Vegf/Map kinase pathway and decreases the expression of HPV oncoproteins E6/E7 through restoration of p53and Rb expression in human cervical cancer cell lines[J].Tumour Biol,2015,37(3):3295-3305.
[6]Poirson J,Biquand E,Straub M L,et al.Mapping the interactome of Hpv E6 and E7 oncoproteins with the ubiquitin-proteasome system[J].FEBS J,2017,284(19):3171-3201.
[7]Chen J,Zhao K N,Li R,et al.Activation of PI3K/Akt/mTORpathway and dual inhibitors of PI3K and mTOR in endometrial cancer[J].Curr Med Chem,2014,21(26):3070-3080.
[8]Spangle J M,Munger K.The HPV16 E6 oncoprotein causes prolonged receptor protein tyrosine kinase signaling and enhances internalization of phosphorylated receptor species[J].PLoSPathog,2013,9(3):1003237-1003248.
[9]Contreras-Paredes A,De La Cruz-Hern Ndez E,MartNez-RamRez I,et al.E6 variants of human papillomavirus 18 differentially modulate the protein kinase B/phosphatidylinositol 3-kinase(AKT/PI3K)signaling pathway[J].Virology,2009,383(1):78-85.
[10]Liu X,Dakic A,Zhang Y,et al.HPV E6 protein interacts physically and functionally with the cellular telomerase complex[J].Proc Natl Acad Sci USA,2009,106(44):18780-18785.
[11]Katzenellenbogen R.Telomerase induction in HPV infection and oncogenesis[J].Viruses,2017,9(7):180-191.
[12]Songyang Z,Fanning A S,Fu C,et al.Recognition of unique carboxyl-terminal motifs by distinct PDZ domains[J].Science,1997,275(5296):73-77.
[13]James C,Roberts S.Viral interactions with PDZ domaincontaining proteins-an oncogenic trait?[J].Pathogens,2016,5(1):8-29.
[14]Thomas M,Myers M P,Massimi P,et al.Analysis of multiple HPV E6 PDZ iInteractions defines type-specific PDZ fingerprints that predict oncogenic potential[J].PLoS Pathog,2016,12(8):1005766-1005786.
[15]Choi M,Lee S,Choi T,et al.Roles of the PDZ domainbinding motif of the human papillomavirus type 16 E6 on the immortalization and differentiation of primary human foreskin keratinocytes[J].Virus Genes,2014,48(2):224-232.
[16]Fan Y,Wang L,Han X,et al.Rab25 is responsible for phosphoinositide 3-kinase/AKT-mediated cisplatin resistance in human epithelial ovarian cancer cells[J].Mol Med Rep,2015,11(3):2173-2178.
[17]Bauman J E,Grandis J R.Targeting secondary immune responses to cetuximab:CD137 and the outside story[J].J Clin Invest,2014,124(6):2371-2375.
[18]Corry J,Bressel M,Fua T,et al.Prospective study of cetuximab,carboplatin,and radiation therapy for patients with locally advanced head and neck squamous cell cancer unfit for cisplatin[J].Int J Radiat Oncol Biol Phys,2017,98(17):948-954.
[19]Abdel-Rahman O.Targeting vascular endothelial growth factor(VEGF)pathway in gastric cancer:preclinical and clinical aspects[J].Crit Rev Oncol Hemat,2015,93(1):18-27.
[20]Monk B J,Sill M W,Burger R A,et al.Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix:a gynecologic oncology group study[J].J Clin Oncol,2009,27(7):1069-1074.
[21]Munagala R,Aqil F,Jeyabalan J,et al.Tanshinone IIA inhibits viral oncogene expression leading to apoptosis and inhibition of cervical cancer[J].Cancer Lett,2015,356(2 Pt B):536-546.
[22]Javadi H,Lotfi A S,Hosseinkhani S,et al.The combinational effect of E6/E7 siRNA and anti-miR-182 on apoptosis induction in HPV16-positive cervical cells[J].Artif Cells Nanomed Biotechnol,2018,6(6):1-10.
[23]Jing K,Shin S,Jeong S,et al.Docosahexaenoic acid induces the degradation of HPV E6/E7 oncoproteins by activating the ubiquitin-proteasome system[J].Cell Death Dis,2014,5(3):1524-1534.
[24]Zhang W,Che Q,Tan H,et al.Marine Streptomyces sp.derived antimycin analogues suppress HeLa cells via depletion HPV E6/E7 mediated by ROS-dependent ubiquitin-proteasome system[J].Sci Rep,2017,7(8):42180-42193.
[25]Network C G A.Comprehensive genomic characterization of head and neck squamous cell carcinomas[J].Nature,2015,517(7536):576-582.
[26]Brand T,Hartmann S,Bhola N,et al.Cross-talk signaling between HER3 and HPV16 E6 and E7 mediates resistance to PI3Kinhibitors in head and neck cancer[J].Cancer Res,2018,78(9):2383-2395.
[27]Mittal S,Banks L.Molecular mechanisms underlying human papillomavirus E6 and E7 oncoprotein-induced cell transformation[J].Mutat Res Rev Mutat Res,2017,772(16):23-35.
[28]Rastogi N,Duggal S,Singh S K,et al.Proteasome inhibition mediates p53 reactivation and anti-cancer activity of 6-Gingerol in cervical cancer cells[J].Oncotarget,2015,6(41):43310-43325.
[29]Petrone L,Ammendolia M G,Cesolini A,et al.Recombinant HPV16 E7 assembled into particles induces an immune response and specific tumour protection administered without adjuvant in an animal model[J].J Transl Med,2011,9(18):69-77.
[30]Mohit E,Bolhassani A,Zahedifard F,et al.The contribution of NT-gp96 as an adjuvant for increasing HPV16 E7-specific immunity in C57BL/6 mouse model[J].Scand J Immunol,2012,75(1):27-37.