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Article(id=1198202433122955850, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198202427301265552, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.0787.2024.0201, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1685980800000, receivedDateStr=2023-06-06, revisedDate=null, revisedDateStr=null, acceptedDate=1692028800000, acceptedDateStr=2023-08-15, onlineDate=1763603321581, onlineDateStr=2025-11-20, pubDate=1730044800000, pubDateStr=2024-10-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763603321581, onlineIssueDateStr=2025-11-20, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763603321581, creator=13701087609, updateTime=1763603321581, updator=13701087609, issue=Issue{id=1198202427301265552, tenantId=1146029695717560320, journalId=1189873630562394117, year='2024', volume='49', issue='10', pageStart='1099', pageEnd='1220', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763603320193, creator=13701087609, updateTime=1763603941762, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1198205034396746241, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198202427301265552, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198205034396746242, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198202427301265552, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1184, endPage=1195, ext={EN=ArticleExt(id=1198202434460938836, articleId=1198202433122955850, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=circ_100284 via miR-217/MAPK1 regulates esophageal squamous cell carcinoma invasion and its effects on 5-FU chemotherapy sensitivity, columnId=1190310110212751762, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Basic Research, runingTitle=null, highlight=null, articleAbstract=

Objective To explore the effects of circ_100284 in affecting the invasion of esophageal squamous cell carcinoma (ESCC) cells and their sensitivity to 5-fluorouracil (5-FU) chemotherapy via regulating miR-217/mitogen-activated protein kinase 1 (MAPK1) acting as a competing endogenous RNA (ceRNA). Methods The bioinformatics approach was used to analyze the differentially expressed circRNAs in ESCC. qRT-PCR was used to detect the expression of circ_100284 in ESCC tissues and cells. The 5-FU-resistant KYSE450 cell line (KYSE45-R) was established by increasing concentrations of 5-FU. The IC50 of 5-FU in KYSE450 and KYSE450-R cells was determined through MTT assay. qRT-PCR was used to detect the expression of circ_100284, miR-217, and MAPK1 mRNA in KYSE450 and KYSE450-R cells, while Western blotting detecting the protein expression of MAPK1. In the experiments with KYSE450-R cells, we set up the following groups: (1) blank group (without treatment), si-NC group (transfected with si-NC), si-circ_100284 group (transfected with si-circ_100284), pc-Control group (transfected with pc-Control), pc-circ_100284 group (transfected with pc-circ_100284), pc-circ_100284+mimic NC group (transfected with pc-circ_100284 and mimic NC), and pc-circ_100284+miR-217 mimic group (transfected with pc-circ_100284 and miR-217 mimic). These groups were subjected to MTT assay to detect cell viability, Transwell assay to detect cell invasion, and flow cytometry to detect cell apoptosis. (2) Blank group (without treatment), si-NC group (transfected with si-MAPK1 negative control), si-MAPK1 group (transfected with si-MAPK1), si-MAPK1+inhibitor NC group (transfected with si-MAPK1 and inhibitor NC), and si-MAPK1+miR-217 inhibitor group (transfected with si-MAPK1 and miR-217 inhibitor). We detected the mRNA and protein expression of MAPK1 using qRT-PCR and Western blotting. We evaluated cell viability using MTT assay, invasion with Transwell assay, and apoptosis by flow cytometry. circ_100284-WT or circ_100284-MUT reporter plasmids, as well as MAPK1-WT or MAPK1-MUT reporter plasmids, were co-transfected with miR-NC or miR-217 mimic into KYSE450-R cells for 48 h, and dual luciferase reporter assay was used to measure luciferase activity. Results The bioinformatics analysis revealed significant upregulation of circ_100284 in ESCC. Compared with adjacent normal tissues, the expression of circ_100284 in ESCC tissues is enhanced (P<0.05); compared with the HECC cells, the TE-11, ECA109 and KYSE450 ESCC cell lines showed enhanced expression of circ_100284 (P<0.05). Compared with the KYSE450 cells, KYSE450-R cells demonstrated increased IC50 with enhanced expression of circ_100284 and MAPK1 but suppressed expression of miR-217 (P<0.05). Compared with the si-NC group, the si-circ_100284 group demonstrated inhibited invasion and proliferation of cells with increased apoptosis (P<0.05). Compared with pc-Control group, the invasion and proliferation of cells in the pc-circ_100284 group are increased, and cell apoptosis is decreased (P<0.05). Over-expression of miR-217 reversed the malignant biological behavior of ESCC cells induced by pc-circ_100284 (P<0.05). Compared with si-NC group, in the si-MAPK1 group, we observed decreased cell invasion and proliferation, and increased apoptosis (P<0.05), but miR-217 inhibitor reversed the effect of si-MAPK1 on the biological behavior of ESCC cells (P<0.05). The targeting relationship of circ_100284 and miR-217, miR-217 and MAPK1 is confirmed. Conclusion circ_100284 promotes ESCC cell invasion by regulating miR-217/MAPK1, inhibits the chemosensitivity of ESCC cells to 5-FU, and acts as a tumor-promoting factor in ESCC.

, correspAuthors=Cai-Feng Mi, authorNote=null, correspAuthorsNote=
E-mail:
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目的 探究环状RNA(circ_100284)作为竞争性内源RNA(ceRNA)通过调控miR-217/丝裂原活化蛋白激酶1(MAPK1)影响食管鳞状细胞癌(ESCC)细胞侵袭及其对5-氟尿嘧啶(5-FU)化疗的敏感性。方法 生物信息学分析ESCC中差异表达的circRNAs。qRT-PCR检测ESCC组织和细胞中circ_100284的表达。使用浓度逐渐增加的5-FU处理ESCC细胞KYSE450以建立5-FU耐药KYSE450细胞系(KYSE450-R)，MTT实验检测KYSE450和KYSE450-R细胞的IC50。qRT-PCR检测KYSE450和KYSE450-R细胞中circ_100284、miR-217和MAPK1 mRNA的表达，Western blotting检测MAPK1蛋白的表达。取KYSE450-R细胞，设置：(1)空白对照组(不做处理)、si-NC组(转染si-NC)、si-circ_100284组(转染si-circ_100284)、pc-Control组(转染pc-Control)、pc-circ_100284组(转染pc-circ_100284)、pc-circ_100284+mimic NC组(转染pc-circ_100284和mimic NC)与pc-circ_100284+miR-217 mimic组(转染pc-circ_100284和miR-217 mimic)，采用MTT实验检测细胞活力，Transwell实验检测细胞侵袭能力，流式细胞术检测细胞凋亡情况。(2)空白对照组(不做处理)、si-NC组(转染si-MAPK1的阴性对照)、si-MAPK1组(转染si-MAPK1)、si-MAPK1+inhibitor NC组(转染si-MAPK1和inhibitor NC)与si-MAPK1+miR-217 inhibitor组(转染si-MAPK1和miR-217 inhibitor)，采用qRT-PCR和Western blotting检测MAPK1 mRNA和蛋白的表达，MTT实验检测细胞活力，Transwell实验检测细胞侵袭能力，流式细胞术检测细胞凋亡情况。将circ_100284-WT或circ_100284-MUT报告质粒、MAPK1-WT或MAPK1-MUT报告质粒分别与miR-NC或miR-217 mimic共转染KYSE450-R细胞48 h，采用双荧光素酶报告实验测定荧光素酶相对活性。结果 生物信息学分析显示circ_100284在ESCC中呈高表达。与癌旁正常组织比较，ESCC组织中circ_100284表达明显增加(P<0.05)；与健康人食管上皮细胞HEEC比较，ESCC细胞系TE-11、ECA09和KYSE450中circ_100284表达明显增加(P<0.05)。与KYSE450细胞比较，KYSE450-R细胞的IC50增加，circ_100284、MAPK1表达增加但miR-217表达被抑制(P<0.05)。与si-NC组比较，si-circ_100284组细胞活力被抑制，细胞侵袭数减少，细胞凋亡率增高(P<0.05)。与pc-Control组比较，pc-circ_100284组细胞活力和细胞侵袭数增加，细胞凋亡率降低(P<0.05)，而pc-circ_100284对ESCC细胞恶性生物学行为的影响被miR-217过表达逆转(P<0.05)。与si-NC组比较，si-MAPK1组细胞活力被抑制，细胞侵袭数减少，细胞凋亡率增高(P<0.05)，而si-MAPK1对ESCC细胞生物学行为的影响被miR-217 inhibitor逆转(P<0.05)。circ_100284与miR-217、miR-217与MAPK1具有靶向关系。结论 circ_100284通过调控miR-217/MAPK1进而增强ESCC细胞的侵袭能力，抑制ESCC细胞对5-FU化疗的敏感性，在ESCC中发挥促癌因子的作用。

, correspAuthors=米彩锋, authorNote=null, correspAuthorsNote=
米彩锋，E-mail：
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史艳伟，副主任医师，主要从事消化道肿瘤方面的研究

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史艳伟，副主任医师，主要从事消化道肿瘤方面的研究

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史艳伟，副主任医师，主要从事消化道肿瘤方面的研究

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ESCC. 食管鳞状细胞癌；HECC. 健康人食管上皮细胞素；A. GSE131969芯片数据中差异表达的circRNAs；B. GSE131969芯片数据中上调表达差异最显著的前10个circRNAs；C. qRT-PCR检测circ_100284在ESCC组织中的表达情况(n=37)；D. qRT-PCR检测circ_100284在ESCC细胞系中的表达情况；与癌旁正常组织比较，(1)P<0.05；与HECC细胞系比较，(2)P<0.05

, figureFileSmall=R49yXgpyf2L393sPMYmRag==, figureFileBig=CDuP+m1Elefh35mEAmSzIg==, tableContent=null), ArticleFig(id=1198319032484065663, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198202433122955850, language=EN, label=Fig.2, caption=Effects of circ_100284 knockdown on the biological behavior of KYSE450 cells, figureFileSmall=zss0CwEQhwJ8NUT3KF13vg==, figureFileBig=cGZN9xgvyl2Dm8jq5TzwDQ==, tableContent=null), ArticleFig(id=1198319032567951747, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198202433122955850, language=CN, label=图2, caption=敲减circ_100284对KYSE450细胞生物学行为的影响

HECC. 健康人食管上皮细胞素；A. MTT实验检测KYSE450和KYSE450-R细胞的IC50；B. qRT-PCR检测circ_100284在KYSE450和KYSE450-R细胞中的表达；C. MTT实验检测各组KYSE450-R细胞活力；D. Transwell实验检测各组细胞侵袭能力；E. 流式细胞术检测各组KYSE450-R细胞凋亡情况；与KYSE450细胞比较，(1)P<0.05；与空白对照组比较，(2)P<0.05；与si-NC组比较，(3)P<0.05

, figureFileSmall=zss0CwEQhwJ8NUT3KF13vg==, figureFileBig=cGZN9xgvyl2Dm8jq5TzwDQ==, tableContent=null), ArticleFig(id=1198319032643449225, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198202433122955850, language=EN, label=Fig.3, caption=circ_100284 adsorbs miR-21 as ceRNA, figureFileSmall=D/m7/AKVCQTIadoC0gINRA==, figureFileBig=VGXen/+Qi+VV7LYwO+OPMw==, tableContent=null), ArticleFig(id=1198319032714752396, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198202433122955850, language=CN, label=图3, caption=circ_100284作为ceRNA吸附miR-21

HECC. 健康人食管上皮细胞素；A. RNase R实验检测circ_100284的降解程度；B. FISH实验检测circ_100284的亚细胞定位；C. Circular RNA Interactome预测circ_100284与miR-217的互补结合序列；D. 双荧光素酶报告实验结果；E. miR-217在37例ESCC组织和癌旁正常组织中的表达；F. Pearson相关性分析miR-217与circ_100284的相关性；G. qRT-PCR检测不同细胞系中miR-217的表达；与RNase R-组比较，(1)P<0.05；与miR-NC组比较，(2)P<0.05；与癌旁正常组织比较，(3)P<0.05；与HECC组比较，(4)P<0.05

, figureFileSmall=D/m7/AKVCQTIadoC0gINRA==, figureFileBig=VGXen/+Qi+VV7LYwO+OPMw==, tableContent=null), ArticleFig(id=1198319032857358736, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198202433122955850, language=EN, label=Fig.4, caption=Effects of circ_100284 on proliferation, invasion and resistance to 5-FU of ESCC cells, figureFileSmall=fOKl31lEqklNoqBbJGW+CA==, figureFileBig=KubbjtupjOGSVqcdwhaOIA==, tableContent=null), ArticleFig(id=1198319032987382163, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198202433122955850, language=CN, label=图4, caption=circ_100284和miR-217对食管鳞状细胞癌细胞生物学行为和5-FU耐药性的影响

5-FU. 5-氟尿嘧啶；A. qRT-PCR检测miR-217在KYSE450-R细胞中的表达；B. MTT实验检测各组细胞活力；C. Transwell实验检测各组细胞侵袭能力；D. 流式细胞术检测各组细胞凋亡率；与KYSE450-R组比较，(1)P<0.05；与pc-Control组比较，(2)P<0.05；与pc-circ_100284+miR-217 mimic组比较，(3)P<0.05

, figureFileSmall=fOKl31lEqklNoqBbJGW+CA==, figureFileBig=KubbjtupjOGSVqcdwhaOIA==, tableContent=null), ArticleFig(id=1198319033088045466, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198202433122955850, language=EN, label=Fig.5, caption=MAPK1 is a direct target of miR-217, figureFileSmall=lWR1NwE5bAEvEwdS4qeU1g==, figureFileBig=mxxGqHMNSVocw2jgRcUXIA==, tableContent=null), ArticleFig(id=1198319033188708762, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198202433122955850, language=CN, label=图5, caption=MAPK1是miR-217的直接靶点

MAPK1. 丝裂原活化蛋白激酶1；A. RNA22和miRDB网站预测结果；B. KEGG通路富集分析；C. 蛋白相互作用分析结果；D. 双荧光素酶分析报告实验结果；E. qRT-PCR检测各组细胞中MAPK1 mRNA表达情况；F. Western blotting检测各组细胞中MAPK1蛋白表达情况；与miR-NC比较，(1)P<0.05；与si-NC组比较，(2)P<0.05；与si-MAPK1+inhibitor NC组比较，(3)P<0.05

, figureFileSmall=lWR1NwE5bAEvEwdS4qeU1g==, figureFileBig=mxxGqHMNSVocw2jgRcUXIA==, tableContent=null), ArticleFig(id=1198319033293566365, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198202433122955850, language=EN, label=Fig.6, caption=miR-217 exerts tumor suppressor effect by negatively regulating MAPK1, figureFileSmall=66bcWERqKeP1+fw2JFjsbQ==, figureFileBig=RnRph6tL+EY0Ztpe0ymN4A==, tableContent=null), ArticleFig(id=1198319033373258144, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198202433122955850, language=CN, label=图6, caption=miR-217通过负调控MAPK1发挥抑癌作用

MAPK1. 丝裂原活化蛋白激酶1；5-FU. 5-氟尿嘧啶；A. qRT-PCR检测MAPK1 mRNA的表达；B. Western blotting检测MAPK1蛋白的表达；C. MTT实验检测细胞活力；D. Transwell实验检测细胞侵袭能力；E. 流式细胞术检测细胞凋亡率；与KYSE450细胞比较，(1)P<0.05；与si-NC组比较，(2)P<0.05；与si-MAPK1+inhibitor NC组比较，(3)P<0.05

, figureFileSmall=66bcWERqKeP1+fw2JFjsbQ==, figureFileBig=RnRph6tL+EY0Ztpe0ymN4A==, tableContent=null), ArticleFig(id=1198319033486504360, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198202433122955850, language=EN, label=Tab.1, caption=

Primer sequences for qRT-PCR

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列(5'-3')
circ_100284正向：ATCCTCCATGGCGGCGATGG
反向：TCGAGTTTCCATAAGAGCCTT
MAPK1正向：AGTCCTCCTAGAGACCCCTTTACCC
反向：TACAGCCTTATAGAGTTTCCATC
GAPDH正向：TATCTTTCCATCAGATCAGCGT
反向：ATATCAGTAAATTCCATTACCAT
miR-217正向：GTAGGATTATCATTAAGGAGTCCTAT
反向：GAGTATCCCAGTCATGTTTATTTT
U6正向：ATTCATTCAGGTTCATGTTTCC
反向：GAGTCCATCATTCCAGTCATCCA
), ArticleFig(id=1198319033587167658, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198202433122955850, language=CN, label=表1, caption=

qRT-PCR引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列(5'-3')
circ_100284正向：ATCCTCCATGGCGGCGATGG
反向：TCGAGTTTCCATAAGAGCCTT
MAPK1正向：AGTCCTCCTAGAGACCCCTTTACCC
反向：TACAGCCTTATAGAGTTTCCATC
GAPDH正向：TATCTTTCCATCAGATCAGCGT
反向：ATATCAGTAAATTCCATTACCAT
miR-217正向：GTAGGATTATCATTAAGGAGTCCTAT
反向：GAGTATCCCAGTCATGTTTATTTT
U6正向：ATTCATTCAGGTTCATGTTTCC
反向：GAGTCCATCATTCCAGTCATCCA
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circ_100284通过miR-217/MAPK1调控食管鳞状细胞癌侵袭及其对5-FU化疗敏感性的影响
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史艳伟 1 , 米彩锋 1, * , 牛丽林 1 , 杨洋 2
解放军医学杂志 | 基础研究 2024,49(10): 1184-1195
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解放军医学杂志 | 基础研究 2024, 49(10): 1184-1195
circ_100284通过miR-217/MAPK1调控食管鳞状细胞癌侵袭及其对5-FU化疗敏感性的影响
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史艳伟1, 米彩锋1, * , 牛丽林1, 杨洋2
作者信息
  • 1平顶山学院第一附属医院/平顶山市第一人民医院消化内科，河南平顶山 467000
  • 2郑州大学第一附属医院胸外科，河南郑州 450052

    • 史艳伟，副主任医师，主要从事消化道肿瘤方面的研究

通讯作者:

米彩锋，E-mail：
circ_100284 via miR-217/MAPK1 regulates esophageal squamous cell carcinoma invasion and its effects on 5-FU chemotherapy sensitivity
Yan-Wei Shi1, Cai-Feng Mi1, * , Li-Lin Niu1, Yang Yang2
Affiliations
  • 1Department of Gastroenterology, the First Affiliated Hospital of Pingdingshan University/Pingdingshan First People's Hospital, Pingdingshan, Henan 467000, China
  • 2Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
出版时间: 2024-10-28 doi: 10.11855/j.issn.0577-7402.0787.2024.0201
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摘要
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目的 探究环状RNA(circ_100284)作为竞争性内源RNA(ceRNA)通过调控miR-217/丝裂原活化蛋白激酶1(MAPK1)影响食管鳞状细胞癌(ESCC)细胞侵袭及其对5-氟尿嘧啶(5-FU)化疗的敏感性。方法 生物信息学分析ESCC中差异表达的circRNAs。qRT-PCR检测ESCC组织和细胞中circ_100284的表达。使用浓度逐渐增加的5-FU处理ESCC细胞KYSE450以建立5-FU耐药KYSE450细胞系(KYSE450-R)，MTT实验检测KYSE450和KYSE450-R细胞的IC50。qRT-PCR检测KYSE450和KYSE450-R细胞中circ_100284、miR-217和MAPK1 mRNA的表达，Western blotting检测MAPK1蛋白的表达。取KYSE450-R细胞，设置：(1)空白对照组(不做处理)、si-NC组(转染si-NC)、si-circ_100284组(转染si-circ_100284)、pc-Control组(转染pc-Control)、pc-circ_100284组(转染pc-circ_100284)、pc-circ_100284+mimic NC组(转染pc-circ_100284和mimic NC)与pc-circ_100284+miR-217 mimic组(转染pc-circ_100284和miR-217 mimic)，采用MTT实验检测细胞活力，Transwell实验检测细胞侵袭能力，流式细胞术检测细胞凋亡情况。(2)空白对照组(不做处理)、si-NC组(转染si-MAPK1的阴性对照)、si-MAPK1组(转染si-MAPK1)、si-MAPK1+inhibitor NC组(转染si-MAPK1和inhibitor NC)与si-MAPK1+miR-217 inhibitor组(转染si-MAPK1和miR-217 inhibitor)，采用qRT-PCR和Western blotting检测MAPK1 mRNA和蛋白的表达，MTT实验检测细胞活力，Transwell实验检测细胞侵袭能力，流式细胞术检测细胞凋亡情况。将circ_100284-WT或circ_100284-MUT报告质粒、MAPK1-WT或MAPK1-MUT报告质粒分别与miR-NC或miR-217 mimic共转染KYSE450-R细胞48 h，采用双荧光素酶报告实验测定荧光素酶相对活性。结果 生物信息学分析显示circ_100284在ESCC中呈高表达。与癌旁正常组织比较，ESCC组织中circ_100284表达明显增加(P<0.05)；与健康人食管上皮细胞HEEC比较，ESCC细胞系TE-11、ECA09和KYSE450中circ_100284表达明显增加(P<0.05)。与KYSE450细胞比较，KYSE450-R细胞的IC50增加，circ_100284、MAPK1表达增加但miR-217表达被抑制(P<0.05)。与si-NC组比较，si-circ_100284组细胞活力被抑制，细胞侵袭数减少，细胞凋亡率增高(P<0.05)。与pc-Control组比较，pc-circ_100284组细胞活力和细胞侵袭数增加，细胞凋亡率降低(P<0.05)，而pc-circ_100284对ESCC细胞恶性生物学行为的影响被miR-217过表达逆转(P<0.05)。与si-NC组比较，si-MAPK1组细胞活力被抑制，细胞侵袭数减少，细胞凋亡率增高(P<0.05)，而si-MAPK1对ESCC细胞生物学行为的影响被miR-217 inhibitor逆转(P<0.05)。circ_100284与miR-217、miR-217与MAPK1具有靶向关系。结论 circ_100284通过调控miR-217/MAPK1进而增强ESCC细胞的侵袭能力，抑制ESCC细胞对5-FU化疗的敏感性，在ESCC中发挥促癌因子的作用。

circ_100284  /  miR-217  /  丝裂原活化蛋白激酶1  /  食管癌  /  化疗敏感性

Objective To explore the effects of circ_100284 in affecting the invasion of esophageal squamous cell carcinoma (ESCC) cells and their sensitivity to 5-fluorouracil (5-FU) chemotherapy via regulating miR-217/mitogen-activated protein kinase 1 (MAPK1) acting as a competing endogenous RNA (ceRNA). Methods The bioinformatics approach was used to analyze the differentially expressed circRNAs in ESCC. qRT-PCR was used to detect the expression of circ_100284 in ESCC tissues and cells. The 5-FU-resistant KYSE450 cell line (KYSE45-R) was established by increasing concentrations of 5-FU. The IC50 of 5-FU in KYSE450 and KYSE450-R cells was determined through MTT assay. qRT-PCR was used to detect the expression of circ_100284, miR-217, and MAPK1 mRNA in KYSE450 and KYSE450-R cells, while Western blotting detecting the protein expression of MAPK1. In the experiments with KYSE450-R cells, we set up the following groups: (1) blank group (without treatment), si-NC group (transfected with si-NC), si-circ_100284 group (transfected with si-circ_100284), pc-Control group (transfected with pc-Control), pc-circ_100284 group (transfected with pc-circ_100284), pc-circ_100284+mimic NC group (transfected with pc-circ_100284 and mimic NC), and pc-circ_100284+miR-217 mimic group (transfected with pc-circ_100284 and miR-217 mimic). These groups were subjected to MTT assay to detect cell viability, Transwell assay to detect cell invasion, and flow cytometry to detect cell apoptosis. (2) Blank group (without treatment), si-NC group (transfected with si-MAPK1 negative control), si-MAPK1 group (transfected with si-MAPK1), si-MAPK1+inhibitor NC group (transfected with si-MAPK1 and inhibitor NC), and si-MAPK1+miR-217 inhibitor group (transfected with si-MAPK1 and miR-217 inhibitor). We detected the mRNA and protein expression of MAPK1 using qRT-PCR and Western blotting. We evaluated cell viability using MTT assay, invasion with Transwell assay, and apoptosis by flow cytometry. circ_100284-WT or circ_100284-MUT reporter plasmids, as well as MAPK1-WT or MAPK1-MUT reporter plasmids, were co-transfected with miR-NC or miR-217 mimic into KYSE450-R cells for 48 h, and dual luciferase reporter assay was used to measure luciferase activity. Results The bioinformatics analysis revealed significant upregulation of circ_100284 in ESCC. Compared with adjacent normal tissues, the expression of circ_100284 in ESCC tissues is enhanced (P<0.05); compared with the HECC cells, the TE-11, ECA109 and KYSE450 ESCC cell lines showed enhanced expression of circ_100284 (P<0.05). Compared with the KYSE450 cells, KYSE450-R cells demonstrated increased IC50 with enhanced expression of circ_100284 and MAPK1 but suppressed expression of miR-217 (P<0.05). Compared with the si-NC group, the si-circ_100284 group demonstrated inhibited invasion and proliferation of cells with increased apoptosis (P<0.05). Compared with pc-Control group, the invasion and proliferation of cells in the pc-circ_100284 group are increased, and cell apoptosis is decreased (P<0.05). Over-expression of miR-217 reversed the malignant biological behavior of ESCC cells induced by pc-circ_100284 (P<0.05). Compared with si-NC group, in the si-MAPK1 group, we observed decreased cell invasion and proliferation, and increased apoptosis (P<0.05), but miR-217 inhibitor reversed the effect of si-MAPK1 on the biological behavior of ESCC cells (P<0.05). The targeting relationship of circ_100284 and miR-217, miR-217 and MAPK1 is confirmed. Conclusion circ_100284 promotes ESCC cell invasion by regulating miR-217/MAPK1, inhibits the chemosensitivity of ESCC cells to 5-FU, and acts as a tumor-promoting factor in ESCC.

circ_100284  /  miR-217  /  mitogen-activated protein kinase 1  /  esophageal cancer  /  chemosensitivity
史艳伟, 米彩锋, 牛丽林, 杨洋. circ_100284通过miR-217/MAPK1调控食管鳞状细胞癌侵袭及其对5-FU化疗敏感性的影响. 解放军医学杂志, 2024 , 49 (10) : 1184 -1195 . DOI: 10.11855/j.issn.0577-7402.0787.2024.0201
Yan-Wei Shi, Cai-Feng Mi, Li-Lin Niu, Yang Yang. circ_100284 via miR-217/MAPK1 regulates esophageal squamous cell carcinoma invasion and its effects on 5-FU chemotherapy sensitivity[J]. Medical Journal of Chinese People’s Liberation Army, 2024 , 49 (10) : 1184 -1195 . DOI: 10.11855/j.issn.0577-7402.0787.2024.0201
正文
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食管癌是消化系统常见的恶性肿瘤[1-3]。食管鳞状细胞癌(esophageal squamous cell carcinoma，ESCC)是食管癌中最为常见的一种类型[4]，临床上常采用化疗药物治疗；然而，耐药性是ESCC治疗中的主要挑战，常导致化疗失败[5]。因此迫切需要探究耐药的分子机制，寻找有效的解决方案。研究发现，非编码RNA在肿瘤发生发展中起着重要作用，形成复杂的调控网络[6]。近年来，环状RNA(circRNA)作为一类特殊的非编码RNA被广泛研究[7-9]，与线性RNA不同，circRNA共价闭合的环形结构使其更稳定，不易被RNA外切酶降解，并且可通过多种机制参与调节转录、转运RNA、结合和翻译蛋白等过程[10-11]。研究显示，在亚坤酸盐诱导正常膀胱细胞恶性转化的过程中，随着亚坤酸盐作用时间的延长，circ_100284在膀胱癌细胞中的表达持续升高，且能够作为竞争性内源RNA(competing endogenous RNA，ceRNA)吸附miR-217促进膀胱癌细胞增殖[12]；也有研究显示，circ_100284能够吸附miR-217进而促进肝癌细胞的恶性生物学行为[13]。此外，在人角质形成细胞癌变进展中，circ_100284可竞争性结合miR-217而调控Zeste同源物增强子2(EZH2)，增强细胞的集落形成、侵袭能力，从而促进癌变进展[14]。因此，circ_100284作为促癌基因在膀胱癌、肝癌、人角质形成细胞癌变进展中发挥作用。研究显示，miR-217可作为抑癌因子参与调控ESCC的进展，且能抑制细胞增殖和侵袭，从而有效抑制ESCC的发展[15-16]。另有研究发现，miR-217与结直肠癌的5-氟尿嘧啶(5-fluorouracil，5-FU)化疗敏感性密切相关[17]。本课题组前期通过生物信息学工具对circ_100284/miR-217潜在的下游mRNA进行预测，发现丝裂原活化蛋白激酶1(mitogen-activated protein kinase 1，MAPK1)与miR-217存在结合位点，而MAPK1在ESCC中的作用及其机制已经初步阐明[18]。因此，本研究探究circ_100284通过miR-217/MAPK1对ESCC细胞生物学功能的作用机制及其对5-FU化疗敏感性的影响，以期为ESCC的治疗提供解决方案。
1 材料与方法
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1.1 主要试剂
反转录试剂盒、实时荧光定量PCR试剂盒、LipofectamineTM 3000试剂盒购自美国Thermo Fisher公司；Trizol试剂、Matrigel基底胶、MTT溶液、结晶紫、化学发光剂购自北京索莱宝科技有限公司；荧光原位杂交(fluorescence in situ hybridization，FISH)探针试剂盒购自上海吉玛基因；DAPI染液购自上海碧云天生物技术有限公司；Annexin V-FITC/PI试剂盒购自北京百奥莱博科技有限公司；一抗MAPK1、山羊抗兔IgG二抗购自英国Abcam公司；蛋白提取试剂盒购自北京碧云天科技有限公司；双荧光素酶报告基因测试盒购自上海北诺生物科技有限公司。
1.2 方法
1.2.1 生物信息学分析
从NCBI数据库查阅并获取ESCC相关GEO芯片表达数据，选择芯片GSE131969。该芯片数据中包含3例ESCC组织及其对应的癌旁正常组织。使用R语言limma包对癌旁正常组织和ESCC组织中差异circRNAs进行分析，差异筛选条件为校正后P<0.05和|log2 FC|>1。在MiRDB(http://mirdb.org/index.html)和RNA22(https://cm.jefferson.edu/rna22/Interactive/)网站获取miRNAs的下游靶基因。采用在线生物信息学工具DAVID6.8(https://david.ncifcrf.gov/home.jsp)进行京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes，KEGG)通路分析。选择校正后P<0.05的通路进行后续分析。借助Venn在线网站(http://bioinformatics.psb.ugent.be/webtools/Venn/)绘制交集。在DisGeNET数据库(https://www.disgenet.org/)获取ESCC的疾病风险基因。String数据库(https://string-db.org)分析蛋白相互作用关系。
1.2.2 组织标本收集
收集2020年1月－2021年12月平顶山市第一人民医院收治的37例ESCC患者的肿瘤组织样本，同期收集癌旁正常组织(远端癌旁正常食管黏膜)作为正常对照。所有患者在标本采集前均未进行放化疗治疗，组织的获取和分离由专门的外科医师进行，并于-80 ℃下保存。标本采集和使用均已获得受试者的知情同意。本研究获平顶山市第一人民医院伦理审查委员会审批(20200007)。
1.2.3 细胞培养与分组
人食管鳞癌细胞系(TE-11、ECA109、KYSE450)及健康人食管上皮细胞系(HEEC)由中国科学院典型培养物保藏委员会细胞库提供，于含100 U/ml青霉素、100 μg/ml链霉素、10%胎牛血清的RPMI-1640培养基中，在37 °C、5% CO2条件下常规培养。将筛选出的细胞株用不同浓度(1、2、5、15、20、30 µg/ml)的5-FU处理，以建立5-FU耐药KYSE450细胞系(KYSE450-R)。
取KYSE450-R细胞，设置：(1)空白对照组(细胞不做处理)、si-NC组(细胞转染si-NC)、si-circ_100284组(细胞转染si-circ_100284)、pc-Control组(细胞转染pc-Control)、pc-circ_100284组(细胞转染pc-circ_100284)、pc-circ_100284+mimic NC组(细胞转染pc-circ_100284和mimic NC)、pc-circ_100284+miR-217 mimic组(细胞转染pc-circ_100284和miR-217 mimic)，采用MTT实验检测细胞活力，Transwell实验检测细胞侵袭能力，流式细胞术检测细胞凋亡情况。(2)空白对照组(细胞不做处理)、si-NC组(细胞转染si-MAPK1的阴性对照)、si-MAPK1组(细胞转染si-MAPK1)、si-MAPK1+inhibitor NC组(细胞转染si-MAPK1和inhibitor NC)、si-MAPK1+miR-217 inhibitor组(细胞转染si-MAPK1和miR-217 inhibitor)，采用qRT-PCR和Western blotting检测MAPK1 mRNA和蛋白的表达，MTT实验检测细胞活力，Transwell实验检测细胞侵袭能力，流式细胞术检测细胞凋亡情况。(3)将circ_100284-WT或circ_100284-MUT报告质粒、MAPK1-WT或MAPK1-MUT报告质粒分别与miR-NC或miR-217 mimic共转染KYSE450细胞48 h，使用双荧光素酶报告试剂盒测定荧光素酶活性。细胞转染步骤借助LipofectamineTM 3000试剂盒完成。
1.2.4 qRT-PCR检测mRNA的表达
采用Trizol试剂提取细胞及组织中的总RNA，按反转录试剂盒说明书步骤反转录合成第1条cDNA，以此cDNA为模板按PCR试剂盒进行PCR反应。引物和探针由广州复能基因科技有限公司设计和合成，采用实时荧光定量PCR试剂盒进行qRT-PCR分析。miR-217以U6作为内参，其他基因的mRNA以GAPDH作为内参，采用2-ΔΔCt法计算各目的基因相对表达量。引物序列如表1所示。
1.2.5 RNase R实验检测circ_100284的降解程度
取总RNA样本中2 μg circ_100284，其中1 μg加入1 μl RNase R，充分反应后加入10× RNase R反应缓冲液。随机将反应体系在37 ℃恒温金属浴中温热10 min，产物用于实时荧光定量PCR检测RNase R的降解程度。
1.2.6 FISH实验检测circ_100284的亚细胞定位
按试剂盒说明书配置相应溶液，将细胞消化离心后均匀置于玻片上用4%多聚甲醛溶液固定15 min；加入0.1%预杂交缓冲液A，室温下反应15 min，吸弃并用PBS清洗2~3次，每次5 min；加入缓冲液C，对细胞进行封闭30 min后吸弃；将配置好的探针混合液与样本在37 ℃下杂交过夜，弃去探针混合液分别加入预热好的F缓冲液、C缓冲液洗涤；加入稀释好的DAPI工作液避光染色15 min，PBS洗涤后滴加抗淬灭剂，在荧光显微镜下对细胞进行观察。
1.2.7 双荧光素酶报告实验验证分子间靶向关系
采用靶向关系预测网站Circular RNA Interactome(https://circinteractome.nia.nih.gov)及Targetscan(https://www.targetscan.org/vert_72/)分别预测miR-217与circ_100284、MAPK1之间的结合位点。利用PCR扩增含有miR-217结合位点的基因的3'UTR序列。将3'UTR克隆到pMIR-REPORT荧光素酶载体pMIR野生型(wild type，WT)质粒中。PCR扩增基因3'UTR结合位点的突变，克隆到pMIR突变型(mutant type，MUT)质粒中。分别构建circ_100284-WT和circ_100284-MUT及MAPK1-WT、MAPK1-MUT。根据LipofectamineTM 3000试剂说明书分别将miR-NC或miR-217 mimic与荧光素酶质粒联合转染。转染48 h后使用双荧光素酶报告基因检测试剂盒测定荧光素酶相对活性。
1.2.8 MTT实验检测细胞活力
根据MTT试剂说明书检测5-FU对各组细胞活力的影响。取转染48 h的各组KYSE450细胞，消化制成单细胞悬液，接种于96孔板中，待细胞贴壁后，用不同浓度(1、2、5、15、20、30 µg/ml)的5-FU处理细胞以构建5-FU耐药KYSE450细胞系(KYSE450-R)。培养48 h后，加入配置好的MTT溶液于37 ℃恒温条件下继续培养4 h，终止后弃去上清液，加入二甲基亚砜振荡15 min，采用酶标仪测定490 nm波长处各孔的吸光度(OD)，绘制细胞生存曲线，并计算5-FU对细胞的半数抑制浓度(half inhibition concentration，IC50)。
1.2.9 Transwell实验检测细胞侵袭能力
将细胞用胰酶消化后计数，PBS清洗，采用无血清培养基制备单细胞悬液。将Matrigel基质胶在冰上与无血清培养基以1∶9体积比共同稀释，预先铺涂于侵袭小室，置于细胞培养箱中恒温培养2 h。在24孔板中加入完全培养基，放入小室，加入单细胞悬液，下室加入含有20% FBS的DMEM培养液，置于24孔板中培养24 h。取出小室用PBS清洗后用乙醇固定滤膜，结晶紫染色后树胶封片。于400倍显微镜下随机选取5个视野计数。
1.2.10 流式细胞术检测细胞凋亡情况
收集各组转染48 h后的细胞，加入30 μg/ml 5-FU作用48 h，胰酶消化后用预冷PBS冲洗，加入结合缓冲液重悬细胞，加入5 μl Annexin V-FITC和PI染液于室温条件下避光反应20 min，再用结合缓冲液冲洗细胞以去除未结合的染料和杂质。在1 h内上流式细胞仪检测细胞凋亡情况。
1.2.11 Western blotting检测蛋白表达情况
采用RIPA裂解液裂解细胞中总蛋白，以100:1加入苯甲基磺酰氟后在4 ℃下、12 000 g离心15 min，上清中加入上样缓冲液，100 ℃煮沸5 min，置于-80 ℃保存，随后进行SDS-PAGE凝胶电泳，湿法转至PVDF膜后加入5% BSA室温封闭1 h，将稀释后的一抗(1:500)孵育至PVDF膜上，4 ℃过夜；弃一抗，TBST洗膜后加入稀释后的辣根过氧化酶标记的山羊抗兔IgG二抗孵育1 h。TBST稀释液洗膜，配置ECL显色液滴加至膜上，在凝胶成像仪下拍照，ImageJ软件进行分析。
1.3 统计学处理
采用SPSS 23.0软件进行统计分析。实验数据以$\bar{x}±s$表示，两组间比较采用t检验，多组间比较采用单因素方差分析，进一步两两比较采用SNK-q检验。采用Pearson相关性分析miR-217与circ_100284的相关性。P<0.05为差异有统计学意义。
2 结果
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2.1 circ_100284在ESCC组织和细胞中的表达
ESCC相关芯片GSE131969中包含566个差异表达的circRNAs(图1A)。选取ESCC中表达上调的前10个circRNAs绘制热图(图1B)，根据右侧条带颜色分析(红色表示高表达，蓝色表示低表达)发现，hsa_circ_100284在ESCC组织中呈高表达。37例ESCC患者年龄62.3(43.4~76.6)岁，其中男23例，女14例；TNM分期：Ⅰ期+Ⅱ期29例，Ⅲ期8例；淋巴结转移7例，未转移30例。qRT-PCR检测结果显示，与癌旁正常组织比较，ESCC组织中circ_100284相对表达水平明显升高(P<0.05，图1C)。与健康人食管上皮细胞系HEEC比较，ESCC细胞系TE-11、ECA109和KYSE450中circ_100284相对表达水平明显升高(P<0.05，图1D)。KYSE450细胞系中circ_100284表达上调最为显著，因此选取KYSE450细胞株进行后续实验。
2.2 敲减circ_100284对ESCC细胞侵袭力及其5-FU敏感性的影响
MTT实验和qRT-PCR检测结果显示，与KYSE450细胞比较，KYSE450-R细胞的IC50及circ_100284表达水平明显增高(P<0.05，图2A、B)。进一步MTT实验检测细胞活力，结果显示，在KYSE450-R细胞中转染si-circ_100284，与空白对照组和si-NC组比较，si-circ_100284组KYSE450-R细胞活力被抑制(P<0.05，图2C)。Transwell实验检测结果显示，与空白对照组和si-NC组比较，si-circ_100284组细胞侵袭数明显减少(P<0.05，图2D)。流式细胞术检测结果显示，与空白对照组和si-NC组比较，si-circ_100284组KYSE452-R细胞凋亡率明显增高(P<0.05，图2E)。空白对照组与si-NC组KYSE450-R细胞活力、细胞侵袭数、细胞凋亡率比较差异均无统计学意义(P>0.05)。
2.3 circ_100284与ESCC中miR-217的关系
RNase R实验结果显示，GAPDH mRNA相对表达水平明显降低(P<0.05)，而circ_100284相对表达水平变化无统计学意义(P>0.05)，提示circ_100284不易被降解，具有环状结构(图3A)。FISH实验检测结果显示，circ_100284主要定位于细胞质中(图3B)，因此circ_100284能够作为ceRNA发挥功能。Circular RNA Interactome预测结果显示，circ_100284与miR-217之间存在互补序列，表明两者可能存在相互作用(图3C)。双荧光素酶报告实验结果显示，circ_100284-WT和miR-217 mimic共转染后相对荧光素酶活性明显降低(P<0.05)，但miR-217 mimic和circ_100284-MUT共转染后相对荧光素酶活性无明显变化(P>0.05，图3D)。与癌旁正常组织比较，ESCC组织中miR-217相对表达水平明显降低(P<0.0001，图3E)，且miR-217的表达与circ_100284呈负相关(r=-0.8494，P<0.0001，图3F)。qRT-PCR检测结果显示，与HEEC细胞系比较，ESCC细胞系TE-11、ECA109和KYSE450中miR-217相对表达水平明显降低(P<0.05，图3G)。
2.4 circ_100284、miR-217对ESCC细胞生物学行为及5-FU耐药性的影响
与KYSE450细胞比较，KYSE450-R细胞中miR-217表达水平明显下调(P<0.05，图4A)。MTT实验和Transwell实验检测结果显示，与pc-Control组比较，pc-circ_100284组细胞活力和细胞侵袭数均明显增加(P<0.05)；与pc-circ_100284+mimic NC组比较，pc-circ_100284+miR-217组细胞活力和细胞侵袭数明显降低(P<0.05，图4B、C)。流式细胞术检测结果显示，与pc-Control组比较，pc-circ_100284组细胞凋亡率明显降低(P<0.05)；与pc-circ_100284+mimic NC组比较，pc-circ_100284+miR-217组细胞凋亡率明显增高(P<0.05，图4D)。
2.5 MAPK1与miR-217的靶向关系验证
在RNA22和miRDB在线靶向关系预测网站获取miR-217的下游靶基因并取交集，共有294个交集靶基因(图5A)。KEGG富集分析结果显示，交集靶基因在癌症通路中显著富集(图5B)。该通路具体富集的12个基因为：MAPK10、GNG4、BDKRB2、FN1、EP300、MAPK1、CTNNB1、ITGAV、RAC1、HIF1A、FGF2和FGFR2。在DisGeNET数据库获取ESCC(CUI：C1142025)的疾病风险基因(ADRA1D、LTA、BRCA1、BRAF)。将癌症通路中的基因与ESCC的疾病风险基因通过String在线预测网站探究基因间的相互作用关系，结果显示，MAPK1和CTNNB1与其他基因间均具有较强的关联性(图5C)。Targetscan预测及双荧光素酶报告实验结果显示，miR-217与MAPK1之间存在特异性结合位点，并且MAPK1-WT和miR-217 mimic共转染后相对荧光素酶活性降低(P<0.05)，但MAPK1-MUT和miR-217 mimic共转染后相对荧光素酶活性无明显变化(P>0.05)，提示miR-217与MAPK1存在靶向关系(图5D)。敲减MAPK1后，MAPK1 mRNA和蛋白相对表达水平明显下调(P<0.05)，而miR-217 inhibitor能部分逆转MAPK1敲减的作用(P<0.05，图5E、F)。
2.6 miR-217、MAPK1对ESCC细胞生物学行为及
5 -FU耐药性的影响
与KYSE450细胞比较，KYSE450-R细胞中MAPK1 mRNA和蛋白相对表达水平明显上调(P<0.05，图6A、B)。MTT实验检测结果显示，与si-NC组比较，si-MAPK1组细胞活力明显降低(P<0.05)；与si-MAPK1+inhibitor NC组比较，si-MAPK1+miR-217 inhibitor组细胞活力明显增高(P<0.05，图6C)。Transwell实验检测结果显示，与si-NC组比较，si-MAPK1组细胞侵袭数明显减少(P<0.05)；与si-MAPK1+inhibitor NC组比较，si-MAPK1+miR-217 inhibitor组细胞侵袭数明显增加(P<0.05，图6D)。流式细胞术检测结果显示，与si-NC组比较，si-MAPK1组细胞凋亡率明显增高(P<0.05)；与si-MAPK1+inhibitor NC组比较，si-MAPK1+miR-217 inhibitor组细胞凋亡率明显降低(P<0.05，图6E)。
3 讨论
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本研究探讨了circ_100284/miR-217靶向MAPK1对ESCC细胞侵袭的影响，以及是否对使用5-FU处理的ESCC细胞的生存及凋亡产生作用，发现circ_100284能够吸附miR-217促进ESCC细胞的侵袭能力，降低ESCC细胞对5-FU化疗药物的敏感性，因此干预circ_100284的表达有望在ESCC化疗中发挥作用。
目前癌细胞的侵袭、转移仍是导致ESCC患者死亡的主要原因之一[19]。研究发现，circRNAs在ESCC的发生发展中起着重要作用[20-22]。而circRNAs的大量研究主要集中于其对ESCC发生、发展、侵袭、转移和其他细胞生物学特征的作用[23]。例如，过表达circ_141539促进了细胞的增殖和侵袭，在食管鳞癌中起致癌作用[24]；circDUSP16基因敲除降低了ESCC细胞的生长速度，进而抑制ESCC的进展[25]。尽管分子生物治疗手段得到广泛应用，但多年来患者的存活率并未得到明显改善[26]。因此，探讨ESCC侵袭的发生机制，寻找全新的生物分子靶点对于ESCC的治疗及预后改善至关重要。本研究通过NCBI数据库获取GEO芯片，筛选出在ESCC组织中异常表达的circRNAs，发现circ_100284在ESCC中呈高表达。circ_100284在膀胱癌、肝癌等癌症中均发挥促癌作用[12-14]，能显著促进癌细胞的侵袭及增殖能力。虽然circ_100284在ESCC中的作用机制尚未阐明，但其下游分子miR-217已被证实与ESCC的发展密切相关，miR-217可抑制ESCC细胞的增殖和侵袭，进而抑制ESCC细胞的成瘤作用[27]。本研究qRT-PCR实验验证了芯片数据的分析结果，circ_100284在ESCC组织中呈高表达，提示其可能作为ESCC的促癌因子参与疾病进程；Transwell实验结果显示，敲减circ_100284可降低ESCC细胞的侵袭能力；FISH实验及双荧光素酶报告实验验证了circ_100284/miR-217之间的靶向关系；进一步通过一系列挽救实验证实circ_100284是通过吸附miR-217进而影响ESCC细胞的功能，miR-217过表达能部分逆转circ_100284过表达对ESCC耐药细胞生物学行为的影响。
为了进一步探究circ_100284/miR-217影响ESCC耐药的具体机制，本研究通过RNA22和miRDB靶向关系在线预测网站获取miR-217的下游靶基因，通过DAVID数据库进行KEGG的功能通路富集分析和疾病风险基因蛋白相互作用分析筛选出miR-217的下游靶基因MAPK1。MAPK1作为激活MAPK通路的重要蛋白之一，能够参与细胞增殖、应激、炎症、分化、功能同步化、转化、凋亡等重要功能[28]。研究发现，miR-574-3p通过调节MAPK1来抑制ESCC细胞的增殖和侵袭[29]。因此，本研究选择MAPK1作为circ_100284/miR-217的下游靶点，进一步证实了miR-217能够调控MAPK1 mRNA和蛋白的表达，通过敲减MAPK1能够抑制耐药ESCC细胞侵袭，而抑制miR-217能部分逆转这一趋势，揭示了circ_100284/miR-217/MAPK1调控轴在ESCC治疗中的意义。
化疗是治疗ESCC的重要临床方法，它能杀死肿瘤细胞，减少肿瘤复发[30]。5-FU是一种常用的治疗ESCC的化疗药物，然而，5-FU耐药性限制了其临床应用[31]。5-FU耐药的分子机制相当复杂，涉及许多基因的表达变化[5]。有研究发现，MAPK1蛋白水平下调后细胞SGC7901/5-FU的生长抑制率明显高于对照组，提示MAPK1可影响癌细胞株对5-FU治疗的敏感性[32]。由此推测，circ_100284可能与5-FU敏感性相关，其能通过吸附miR-217降低MAPK1的表达，从而影响ESCC细胞对5-FU的敏感性。
综上所述，本研究揭示了circ_100284/miR-217/MAPK1轴在ESCC进展中的机制，证实了si-circ_100284在ESCC细胞中的抑癌作用及其在促进细胞5-FU敏感中的作用，为ESCC的治疗提供了一定的理论基础和新的有效靶点。但本研究存在不足之处，如未进行体内实验等，今后需进一步完善。
基金
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  • 吴阶平医学基金(24210006)
文献
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参考文献 引证文献
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2024年第49卷第10期
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doi: 10.11855/j.issn.0577-7402.0787.2024.0201
  • 接收时间：2023-06-06
  • 首发时间：2025-11-20
  • 出版时间：2024-10-28
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  • 收稿日期：2023-06-06
  • 录用日期：2023-08-15
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Wu Jieping Fund(24210006)
吴阶平医学基金(24210006)
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    1平顶山学院第一附属医院/平顶山市第一人民医院消化内科，河南平顶山 467000
    2郑州大学第一附属医院胸外科，河南郑州 450052

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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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