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Article(id=1218263657872543889, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263653049094254, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2017-0212, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1488988800000, receivedDateStr=2017-03-09, revisedDate=1493654400000, revisedDateStr=2017-05-02, acceptedDate=null, acceptedDateStr=null, onlineDate=1768386290281, onlineDateStr=2026-01-14, pubDate=1505145600000, pubDateStr=2017-09-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1768386290281, onlineIssueDateStr=2026-01-14, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1768386290281, creator=13701087609, updateTime=1768386290281, updator=13701087609, issue=Issue{id=1218263653049094254, tenantId=1146029695717560320, journalId=1189982191388893191, year='2017', volume='52', issue='9', pageStart='1351', pageEnd='1484', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1768386289131, creator=13701087609, updateTime=1768386664469, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1218265227385295605, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263653049094254, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1218265227385295606, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263653049094254, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1372, endPage=1378, ext={EN=ArticleExt(id=1218263658434580632, articleId=1218263657872543889, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Advances in the study of SORCIN in cancer drug resistance, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=REVIEWS, runingTitle=null, highlight=null, articleAbstract=

Soluble resistance-related calcium-binding protein, SORCIN, is a 22 kDa calcium binding protein with "penta-EF hand", which participates in the regulation of intracellular calcium homeostasis in cells. SORCIN is highly expressed in many tissues such as hearts and brains. It is overexpressed in some of cancer tissues as well. Recently, a large amount of clinical data showed that SORCIN was closely related to drug resistance in cancer. Meanwhile, basic research found that SORCIN participates in the formation of multidrug resistance (MDR) and is related to severity and poor prognosis of tumors. Moreover, it may also regulate MDR induced by ATP-binding cassette transporters. Therefore, SORCIN is expected to become a new target for diagnosis and treatment of MDR. The present review summarizes recent progress in SORCIN study and its effect on MDR.

, correspAuthors=Ke-xin LIU, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2017 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Yao-ting SUN, Ke-xin LIU), CN=ArticleExt(id=1218263659156000933, articleId=1218263657872543889, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=SORCIN与肿瘤耐药及耐药相关转运体研究进展, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

可溶性耐药相关钙结合蛋白（soluble resistance-related calcium-binding protein，SORCIN）是一个22kDa的具有典型"EF-hand"结构的钙结合蛋白，参与细胞内钙稳态调节。SORCIN广泛分布于多种组织，其中在正常的心脏与脑组织中高表达，而在部分肿瘤组织中过表达。近年来，大量的临床数据显示SORCIN与肿瘤耐药性密切相关。基础研究表明SORCIN不仅参与肿瘤细胞多药耐药（multidrug resistance，MDR）的形成，且与肿瘤的恶性程度、不良预后密切相关。此外，部分研究证明SORCIN参与ATP结合盒转运体（ABC transporter）的调节，进而对肿瘤耐药性产生影响。因此，SORCIN有望成为肿瘤耐药诊断及治疗的新靶点。本文对SORCIN及其在肿瘤耐药方面的研究进展进行综述。

, correspAuthors=刘克辛, authorNote=null, correspAuthorsNote=
* 刘克辛, Tel/Fax:86-411-86110407, E-mail:
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Cell line Selected drug SORCIN Transporter Disease
CCRF-CEM/MTX[17] Methotrexate + Not given Leukemia
K562/A02[20, 29] Doxorubicin + P-gp Leukemia
K562/VCR[24] Vincristine + P-gp Leukemia
ARH77/Vin[35] Vincristine + Not given Leukemia
ARHD60/DX[35] Doxorubicin + Not given Leukemia
U937/Vin[35] Vincristine − Not given Leukemia
Jurkat/DX[35] Doxorubicin − Not given Leukemia
HOB1/VCR1.0[36] Vincristine + P-gp Lymphoma
HOB1/VCR0.5[36] Vincristine − P-gp Lymphoma
DLBCL/CHOP[37] Cytoxan + Not given Lymphoma
MCF-7/A02[29] Doxorubicin + P-gp Breast cancer
MCF-7/PAC[19] Paclitaxel + P-gp Breast cancer
SGC7901/VCR[38] Vincristine + P-gp Gastric cancer
KM3/DDP[23] Cisplatin + P-gp, MRP1 Myeloma
U266/ADM[23] Doxorubicin + P-gp, MRP1 Myeloma
A549-T24[39] Paclitaxel + Not given Lung cancer
A549/DDP[22] Cisplatin + P-gp, MRP1, LRP, ABCA2, ABCA5 Lung cancer
NCI-H446/CDDP[40] Cisplatin + Not given Lung cancer
H460/GEM[15] Gemcitabine + Not given Lung cancer
SKOV3-TR30[41] Paclitaxel + Not given Ovarian cancer
Hela/VCR[42] Vincristine + P-gp Cervical cancer
CNE2/DDP[43] Cisplatin + P-gp, MRP1 Nasopharynx cancer
), ArticleFig(id=1218968460567167511, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263657872543889, language=CN, label=Table 1, caption=

Expression of soluble resistance-related calcium-binding protein (SORCIN) and transporters in drug-resistance cells

, figureFileSmall=null, figureFileBig=null, tableContent=
Cell line Selected drug SORCIN Transporter Disease
CCRF-CEM/MTX[17] Methotrexate + Not given Leukemia
K562/A02[20, 29] Doxorubicin + P-gp Leukemia
K562/VCR[24] Vincristine + P-gp Leukemia
ARH77/Vin[35] Vincristine + Not given Leukemia
ARHD60/DX[35] Doxorubicin + Not given Leukemia
U937/Vin[35] Vincristine − Not given Leukemia
Jurkat/DX[35] Doxorubicin − Not given Leukemia
HOB1/VCR1.0[36] Vincristine + P-gp Lymphoma
HOB1/VCR0.5[36] Vincristine − P-gp Lymphoma
DLBCL/CHOP[37] Cytoxan + Not given Lymphoma
MCF-7/A02[29] Doxorubicin + P-gp Breast cancer
MCF-7/PAC[19] Paclitaxel + P-gp Breast cancer
SGC7901/VCR[38] Vincristine + P-gp Gastric cancer
KM3/DDP[23] Cisplatin + P-gp, MRP1 Myeloma
U266/ADM[23] Doxorubicin + P-gp, MRP1 Myeloma
A549-T24[39] Paclitaxel + Not given Lung cancer
A549/DDP[22] Cisplatin + P-gp, MRP1, LRP, ABCA2, ABCA5 Lung cancer
NCI-H446/CDDP[40] Cisplatin + Not given Lung cancer
H460/GEM[15] Gemcitabine + Not given Lung cancer
SKOV3-TR30[41] Paclitaxel + Not given Ovarian cancer
Hela/VCR[42] Vincristine + P-gp Cervical cancer
CNE2/DDP[43] Cisplatin + P-gp, MRP1 Nasopharynx cancer
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SORCIN与肿瘤耐药及耐药相关转运体研究进展
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孙耀庭 , 刘克辛 *
药学学报 | 综述 2017,52(9): 1372-1378
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药学学报 | 综述 2017, 52(9): 1372-1378
SORCIN与肿瘤耐药及耐药相关转运体研究进展
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孙耀庭, 刘克辛*
作者信息
  • 大连医科大学药学院, 辽宁 大连 116044

通讯作者:

* 刘克辛, Tel/Fax:86-411-86110407, E-mail:
Advances in the study of SORCIN in cancer drug resistance
Yao-ting SUN, Ke-xin LIU*
Affiliations
  • College of Pharmacy, Dalian Medical University, Dalian 116044, China
出版时间: 2017-09-12 doi: 10.16438/j.0513-4870.2017-0212
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摘要
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可溶性耐药相关钙结合蛋白（soluble resistance-related calcium-binding protein，SORCIN）是一个22kDa的具有典型"EF-hand"结构的钙结合蛋白，参与细胞内钙稳态调节。SORCIN广泛分布于多种组织，其中在正常的心脏与脑组织中高表达，而在部分肿瘤组织中过表达。近年来，大量的临床数据显示SORCIN与肿瘤耐药性密切相关。基础研究表明SORCIN不仅参与肿瘤细胞多药耐药（multidrug resistance，MDR）的形成，且与肿瘤的恶性程度、不良预后密切相关。此外，部分研究证明SORCIN参与ATP结合盒转运体（ABC transporter）的调节，进而对肿瘤耐药性产生影响。因此，SORCIN有望成为肿瘤耐药诊断及治疗的新靶点。本文对SORCIN及其在肿瘤耐药方面的研究进展进行综述。

可溶性耐药相关钙结合蛋白  /  多药耐药  /  ATP结合盒转运体  /  P-糖蛋白  /  钙稳态

Soluble resistance-related calcium-binding protein, SORCIN, is a 22 kDa calcium binding protein with "penta-EF hand", which participates in the regulation of intracellular calcium homeostasis in cells. SORCIN is highly expressed in many tissues such as hearts and brains. It is overexpressed in some of cancer tissues as well. Recently, a large amount of clinical data showed that SORCIN was closely related to drug resistance in cancer. Meanwhile, basic research found that SORCIN participates in the formation of multidrug resistance (MDR) and is related to severity and poor prognosis of tumors. Moreover, it may also regulate MDR induced by ATP-binding cassette transporters. Therefore, SORCIN is expected to become a new target for diagnosis and treatment of MDR. The present review summarizes recent progress in SORCIN study and its effect on MDR.

soluble resistance-related calcium-binding protein  /  multidrug resistance  /  ATP-binding cassette transporter  /  P-glycoprotein  /  calcium homeostasis
孙耀庭, 刘克辛. SORCIN与肿瘤耐药及耐药相关转运体研究进展. 药学学报, 2017 , 52 (9) : 1372 -1378 . DOI: 10.16438/j.0513-4870.2017-0212
Yao-ting SUN, Ke-xin LIU. Advances in the study of SORCIN in cancer drug resistance[J]. Acta Pharmaceutica Sinica, 2017 , 52 (9) : 1372 -1378 . DOI: 10.16438/j.0513-4870.2017-0212
正文
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化疗是癌症治疗的重要手段, 多数情况下化疗初期是有效的, 但随着给药时间延长或者在肿瘤复发后再应用化疗药物, 肿瘤往往不再对化疗敏感。与此同时, 该种情况下的肿瘤不仅对一种药物产生抵抗, 同时对多种结构不同、作用机制不同的药物也产生抵抗, 这种耐药现象被称为肿瘤的多药耐药(multidrug resistance, MDR)。肿瘤耐药及逆转其耐药是癌症研究领域的热点与难点。关于肿瘤耐药的机制及其逆转方法的研究主要集中于ATP盒转运体家族(ABC transporters), 而近几年研究发现, 可溶性耐药相关钙结合蛋白(soluble resistance-related calcium-binding protein, SORCIN)与肿瘤耐药同样密切相关, 因此本文将从SORCIN的基本性质及生物学功能、SORCIN对肿瘤耐药的调节及其与ABC转运体的关系、以SORCIN为靶点的逆转耐药研究这几方面对SORCIN近年来的研究进行系统的综述。
1 SORCIN概述
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SORCIN也被称为V19或p21, 于1981年在中国仓鼠肺癌耐紫杉醇细胞系DC-3F/VCRd-5L中被首次发现[1]。它是一个22 kDa的具有典型“EF-hand”结构的钙结合蛋白[2]。SORCIN在哺乳动物间的表达具有高度的保守性[3]。小鼠和人的氨基酸序列有8个氨基酸差异, 其中6个与可磷酸化的残基相关, 说明SORCIN的磷酸化具有种属特异性[4]。SORCIN可与多种丝苏氨酸激酶结合, 并被其磷酸化, 如polo样激酶1 (polo-like kinase, PLK1)、cAMP依赖的蛋白激酶A (cAMP-dependent protein kinase, PKA)、钙/钙调蛋白激酶Ⅱ (calcium-calmodulin dependent kinase Ⅱ, CaMK Ⅱ)。
SORCIN分布于正常的人体组织如脑、心脏、淋巴细胞、单核细胞、肾脏、乳腺和皮肤, 其中在脑和心脏呈高表达。此外, SORCIN还广泛分布于肿瘤耐药细胞, 呈现过表达。它在细胞内的位置并非固定不动, 而是呈现动态变化, 比如在细胞有丝分裂间期时位于细胞核、胞浆、质膜、内质网及内质网分泌的囊泡内; 在分裂末期, SORCIN浓集于卵裂沟[5]。
SORCIN的主要功能是参与肿瘤耐药与细胞内钙离子稳态的调节。它通过两种方式调节细胞内钙离子稳态。其中一种是自身与钙离子结合, 结合钙离子的能力可高达微摩尔级, 这一点被直接钙结合实验所证实[6]。而另外一种则是以钙依赖的方式通过与细胞内钙离子通道或其他蛋白的结合进而间接调节细胞内钙离子的释放。可以与之结合的离子通道或蛋白有:兰尼碱受体(ryanodine receptors, RyRs)[7]、肌浆网钙离子转运ATP酶(sarcoendoplasmic reticulum calcium transport ATPase, SERCA)[8]、电压门控L型钙通道(voltage-dependent L-type Ca2+ channels, L-type VDCC)[9]、质膜钠钙交换体(Na+-Ca2+ exchangers, NCX)[10]。当SORCIN与以上蛋白发生结合时, 可以调控以上通道或蛋白的功能, 调节内质网对钙离子的储存与释放, 由此引发细胞内部进一步的生命活动。SORCIN作为一个胞浆蛋白, 当它与钙离子结合后, 构象发生改变, 疏水性结构外翻, 蛋白从胞质向质膜转移, 同时与某些特定蛋白结合参与细胞内信号转导与调节。
SORCIN除了调节胞内钙离子稳态, 同时参与多种疾病的进程。
在糖尿病方面, 高脂饮食下过表达SORCIN可增加葡萄糖耐受、阻止内质网应激的发生、抵抗脂毒性引起的胰岛β细胞凋亡, 因此, 提高SORCIN表达和活性的药物可增加胰岛素分泌保护β细胞[3]。
在1-甲基-4-苯基吡啶离子(MPP+)诱导的SH-SY5Y细胞帕金森病模型中, 对亲本细胞与诱导细胞进行蛋白组学分析, 结果发现SORCIN的表达明显上调, 作者认为细胞内钙离子在MPP+诱导后上升, SORCIN表达增加后可以与上升的钙离子结合, SORCIN在此作为避免钙离子超载的应激防御表达[11]。Tau蛋白是阿尔茨海默症的病理标志蛋白, 可以与SORCIN相互作用, 削弱SORCIN对内质网应激的防御, 影响阿尔茨海默症的形成[12]。
在病毒感染方面, SORCIN作为重要的宿主因子, 参与病毒的增殖。SORCIN可与口蹄疫病毒的VP1蛋白相互作用, 通过抑制TNF-α、仙台病毒所致的Ⅰ型干扰素反应、NF-κB启动子, 减慢宿主抗病毒的炎症反应, 调低免疫应答, 最终引起感染。抑制宿主SORCIN的表达后, 可以抑制感染[13]。另一个实验证明, SORCIN与丙型肝炎病毒的NS5A蛋白相互作用, 通过抑制SORCIN的表达可以降低丙肝病毒的传染性[14]。
2 SORCIN与MDR现象的关系
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关于SORCIN参与肿瘤多药耐药, 近年来赢得越来越多的关注。SORCIN已被证实在多种癌症耐药细胞中呈现过表达状态, 与肿瘤的恶性程度、不良预后直接相关。
体内研究中, Qu等[15]对62例非小细胞肺癌样本进行免疫组化分析, 其中66.1%的样本可见SORCIN表达。同时作者又将临床样本分为吉西他滨敏感组(n=26) 和吉西他滨耐药组(n=36), 在吉西他滨耐药组中, SORCIN的表达阳性率为83.3%, 结果说明SORCIN过表达与吉西他滨耐药密切相关。此外, 作者还考察了SORCIN阴性表达和阳性表达的患者生存情况, 结果发现SORCIN表达阴性的患者生存期明显长于SORCIN阳性表达的患者生存期。耐药的产生是导致肿瘤恶性程度高、不良预后的重要因素, 因此SORCIN对耐药的影响在某种程度上来讲也是对肿瘤恶性程度及不良预后的影响。有研究者通过对乳腺癌患者血清样本进行双向凝胶电泳发现, SORCIN在耐药患者中的表达高达70%, 而在正常乳腺癌组织中几乎不表达, 说明SORCIN与肿瘤耐药可能相关[16]。另有临床数据统计发现, 在儿童急性淋巴细胞性白血病(acute lymphoblastic leukemia, ALL)中, 新确诊的ALL患者中SORCIN mRNA的表达与未患病者无明显差别。而当SORCIN高表达时, 肿瘤耐药的风险相比于不耐药增加了6.8倍。该临床结果表明, SORCIN的表达与肿瘤耐药性正相关[17]。在急性髓性白血病(acute myelogenous leukemia, AML)中, SORCIN (−)患者的完全缓解率比SORCIN (+)明显升高(P < 0.001)[18]。
体外研究中, 研究者利用蛋白质组学方法比对敏感细胞与耐药细胞蛋白表达的差异发现, 在MCF-7/ PAC乳腺癌耐紫杉醇细胞系[19]、K562/A02白血病耐阿霉素细胞系[20]、H460/GRM肺癌耐吉西他滨细胞系[15]、SGC7901/VCR胃癌耐长春新碱细胞系[21]中SORCIN均呈现过表达状态。在甲氨蝶呤(methotrexate, MTX)诱导的人类T淋巴细胞白血病细胞系(human T-lymphoblastic leukemia cell line)中, 随着MTX诱导浓度的增加, SORCIN的表达也随之增加[17]。许多实验证明, 当运用RNAi技术将耐药细胞株中SORCIN基因沉默后, 细胞对药物的敏感性明显增加[22, 23], 当在敏感株中转染表达SORCIN后, 细胞对药物敏感性降低[24]。向无SORCIN表达的K562敏感细胞株中转染SORCIN基因, 细胞对多种药物产生耐药, 包括多柔比星、依托泊苷、高三尖杉酯碱、长春新碱, 耐药倍数增加4.1至22.5倍不等[25]。
以上体内、体外结果证实, SORCIN与肿瘤耐药密切相关, 参与肿瘤耐药的发生与发展。
3 SORCIN引起耐药的可能机制
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SORCIN可能通过多种途径参与肿瘤的多药耐药产生, 目前研究情况如下。
3.1 增加药物外排转运体的表达
SORCIN表达的增加或减少可以引起P-gp及其他外排转运体表达及功能的改变。具体内容介绍参看本文4.1项。
3.2 降低内质网应激损伤与减少细胞凋亡
SORCIN以两种形式存在于细胞内, 一种是22 kDa存在于胞浆的蛋白, 另一种是18 kDa存在于线粒体的蛋白。最新研究发现, 当乳腺癌细胞转染了具有内质网应激保护作用的蛋白TRAP1后, 可以引起线粒体内18 kDa SORCIN增加, 从而减少由内质网应激及药物毒性引起的细胞凋亡[26], 同时还发现在结肠癌细胞中沉默SORCIN后, 可以增加TRAP1蛋白的降解, 提高细胞对毒性药物的敏感性从而引起凋亡[27]。22 kDa SORCIN也扮演着同样的角色, 其参与内质网应激的保护, 阻止线粒体转换孔(mitochondrial transition pore, mtPTP)孔道的开放。将22 kDa SORCIN下调后, 可以激活caspase-3、caspase-12及GRP78/BiP, 启动线粒体凋亡通路[28]。另有研究报道, 通过流式细胞术检测细胞凋亡发现, 沉默SORCIN后相比于对照组可以显著增加细胞凋亡比例, 同时增加线粒体促凋亡蛋白bax表达, 减少抗凋亡蛋白Bcl-2的表达[29]。
3.3 调节细胞周期
多个研究发现, 当SORCIN沉默后细胞周期将会阻滞于G2/M期[22]。细胞周期调控在肿瘤细胞的发生发展至关重要。细胞会在G2/M期检验点审查DNA是否有损伤, 当细胞发生DNA损伤时, 细胞会大量阻滞于G2/M期, 如DNA损伤未能得到及时的修复, 细胞将进入凋亡阶段。有研究者在成纤维细胞中发现, SORCIN可以与PLK1共同作用调节细胞周期, 沉默SORCIN后使得G2/M期细胞比例增加, 同时降低细胞的增殖[5]。
4 SORCIN与肿瘤耐药转运体的关系
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药物转运体介导的MDR是目前研究最为深入的肿瘤耐药机制之一。绝大多数的耐药细胞均存在外排性转运体如P-gp、MRP1、MRP2不同程度的表达, 这些转运体可以将结构不同、作用机制不同的药物排出细胞外, 从而引起肿瘤细胞内药物浓度降低, 影响化疗药物对肿瘤细胞的毒性作用[30-32]。SORCIN基因位于7号染色体上, 与编码P-gp的MDR1基因在同一个同源染色区均匀着色区(homogeneously staining regions, HSRs)[33]。SORCIN被定义为耐药相关蛋白, 也是因为二者的共扩增现象而命名的。
有许多临床与基础实验研究探讨二者之间的关系。从多组临床胃癌组织样本免疫组化染色及相关性分析显示, P-gp与SORCIN的表达密切相关[34]。在AML患者中, 统计学相关性表明SORCIN与MDR1的表达密切相关(r=0.841, P < 0.001)[18]。SORCIN与转运体在肿瘤耐药细胞中的表达情况总结见表 1。
4.1 SORCIN对肿瘤耐药转运体的影响
有研究者[23]通过shRNA介导的基因沉默技术, 检测U266/ADM骨髓瘤耐多柔比星及KM3/DDP骨髓瘤耐顺铂细胞系中SORCIN表达降低时细胞药物敏感性与转运体的变化情况。结果显示, 当沉默SORCIN后, 细胞对药物敏感性增加, 作者通过蛋白印记实验发现P-gp、MRP1的表达降低, 通过流式细胞术观察到P-gp的经典荧光底物罗丹明-123的胞内蓄积增加, 以上结果表明SORCIN可以直接或者间接调控P-gp的表达。其他课题组在CNE2/DDP鼻咽癌耐顺铂的细胞中发现了同样的结果[43]。此外, 在A549/DDP肺癌耐顺铂细胞系中, 研究者同样发现, 当通过RNAi技术沉默SORCIN表达后, 除了P-gp、MRP1表达降低及罗丹明-123蓄积增加外, 还会引起肺耐药相关蛋白LRP、ABCA2蛋白、ABCA5蛋白的表达减少[22]。
在SGC7901/VCR胃癌耐长春新碱细胞株中, 作者分别向不表达SORCIN的敏感株内转入SORCIN基因, 向过表达SORCIN的耐药株中沉默SORCIN, 结果发现转入SOCIN后, 维拉帕米可以逆转耐药现象, 进一步结果发现P-gp随着SORCIN的转入而增加, 随着其沉默而减少[24]。
以上实验内容从多个角度证明了SORCIN可以调节P-gp、MRP1等药物外排转运体的表达, 从而改变细胞内药物的浓度, 最终影响药物的疗效。
4.2 肿瘤耐药转运体对SORCIN的影响
上述几组实验均证明了SORCIN可以调控P-gp表达且表达趋势的方向一致, 但是只是单纯考察了SORCIN对P-gp的影响, 并未说明P-gp对SORCIN的影响。有研究者通过采用不同浓度的长春新碱诱导HOB1细胞, 结果发现当长春新碱浓度是0.1 μmol·L−1时, MDR1就已经开始扩增, 当浓度逐渐提高到0.5、0.75和1.0 μmol·L−1时, MDR1也随之增加。而SORCIN仅在最高浓度1.0 μmol·L−1时出现。当把耐药细胞置于含有0.1 μmol·L−1长春新碱培养基中培育一段时间后, 细胞耐药性降低, SORCIN表达也随之降低。该现象说明, SORCIN参与细胞耐药, 但MDR1对SORCIN的表达可能没有影响[36]。在另一项实验中, 作者分别在K562/A02与MCF-7/A02细胞中抑制SORCIN和MDR1基因, 然后考察这两种蛋白的表达情况及对药物敏感性。结果显示, 沉默SORCIN后两种细胞均可增加对5种抗肿瘤药物的敏感性, 但对P-gp表达不产生影响, 这与其他课题组做出的结果不尽相同, 即沉默SORCIN可以降低P-gp表达。此外, 沉默P-gp对SORCIN的表达也没有影响[29]。该现象提示, SORCIN除了对药物转运体的影响, 还可能存在其他机制。值得注意的是, 在一株非典型的卵巢癌长春新碱耐药细胞中, SORCIN高表达, 而P-gp几乎不表达[44]。这种现象的发现在一定程度上削弱了SORCIN与P-gp的关系, 但这也可能只是一个个例。
以上证据说明, SORCIN可能会成为一个潜在的逆转MDR的治疗靶点。然而, SORCIN与转运体的调节仍存在许多争议, 这可能是由于不同肿瘤细胞之间的差异所导致的, 仍需进一步的研究与探讨。
4.3 SORCIN对肿瘤耐药转运体调控机制研究
研究发现, 在K562/ADR与K562/VCR耐药株中SORCIN呈过表达, 当沉默SORCIN后, 可引起P-gp表达减少。而在K562敏感株中, SORCIN几乎不表达, 通过质粒转染表达SORCIN后, P-gp表达也随之增加。进一步实验证实了SORCIN一方面可以调节mdr1/P-gp启动子处的cAMP反应元件(CRE)来调控mdr1/p-gp的表达, 另一方面它还通过增加p-CREB1与mdr1启动子的CRE序列结合增加P-gp表达[24]。
虽然目前对SORCIN的研究并不多, 但现有的研究提示SORCIN可调节P-gp转运体的表达; 其他非肿瘤类的研究提示, SORCIN可能是通过对转录因子NF-κB的调节间接影响MDR1基因与P-gp蛋白的表达[13]。但SORCIN在肿瘤细胞中如何调节转运体表达的具体机制, 目前尚无相关研究。
5 药物对SORCIN的调节研究
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海生素是从海洋生物泥蚶中提取的蛋白质, 目前已被批准进入临床。体内实验证明, 海生素对急性淋巴细胞白血病具有良好的抗肿瘤效果, 体外研究发现, 海生素可以抑制K562/ADM的P-gp与SORCIN的表达, 并具有剂量依赖性[45, 46]。
钙通道阻滞剂汉防己甲素(tetrandrine, Tet)能够逆转肿瘤多药耐药, 临床效果好且不良反应小。为探讨其可能的逆转机制, 作者选用了K562/A02细胞株, 给予0.5、1.0、2.0 mg·L−1的Tet, 48 h后测SORCIN的mRNA与蛋白表达情况。结果显示, 1.0 mg·L−1浓度下对SORCIN的抑制作用最强, 并不呈剂量依赖性, 由此推测Tet逆转耐药可能还有其他因素参与[47]。
靛玉红衍生物PHⅡ-7是中药当归龙荟丸主要抗肿瘤活性成分, 该药对耐药细胞尤其敏感, 2 mg·L−1 PHⅡ-7处理K562/A02细胞24 h后, SORCIN的表达几乎被完全抑制, 而MDR1的表达则被完全抑制[48]。
临床试验研究发现, 多发性骨髓瘤患者SORCIN表达阳性率为75%, 给予P-gp经典抑制剂环孢菌素A治疗后阳性率为62.5%, 无统计学差异, 说明环孢菌素A对SORCIN的表达无影响[49]。
6 总结与展望
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肿瘤多药耐药严重阻碍了化疗药物的有效性, 克服并逆转肿瘤多药耐药是当今肿瘤研究的热门领域, 同时对人类来说也是一个艰巨的挑战。SORCIN与肿瘤的耐药性密切相关, 关于其产生耐药的机制仍不明确。可以肯定的是, 抑制SORCIN可以逆转肿瘤的耐药性。因此, SORCIN有望成为一个新的肿瘤耐药性及癌症预后的评估指标。虽然目前SORCIN对MDR的调节机制并不完全清楚, 但相信随着研究的深入, 以SORCIN为靶点设计逆转肿瘤耐药药物将为克服与治疗肿瘤耐药开辟新途径。
基金
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  • 国家自然科学基金资助项目(81473280)
文献
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2017年第52卷第9期
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doi: 10.16438/j.0513-4870.2017-0212
  • 接收时间：2017-03-09
  • 首发时间：2026-01-14
  • 出版时间：2017-09-12
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  • 收稿日期：2017-03-09
  • 修回日期：2017-05-02
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国家自然科学基金资助项目(81473280)
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    大连医科大学药学院, 辽宁 大连 116044

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* 刘克辛, Tel/Fax:86-411-86110407, E-mail:
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2种不同金属材料的力学参数
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Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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