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Article(id=1240710435742216598, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2024.10.11, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1678636800000, receivedDateStr=2023-03-13, revisedDate=null, revisedDateStr=null, acceptedDate=1717257600000, acceptedDateStr=2024-06-02, onlineDate=1773738019166, onlineDateStr=2026-03-17, pubDate=1729785600000, pubDateStr=2024-10-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773738019166, onlineIssueDateStr=2026-03-17, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773738019166, creator=13701087609, updateTime=1773738019166, updator=13701087609, issue=Issue{id=1240710432898478399, tenantId=1146029695717560320, journalId=1205117082300743687, year='2024', volume='43', issue='10', pageStart='721', pageEnd='800', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773738018488, creator=13701087609, updateTime=1773738214158, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1240711253669237259, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1240711253669237260, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=790, endPage=795, ext={EN=ArticleExt(id=1240710435985486249, articleId=1240710435742216598, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=Impact of erianin on occurrence and development of pancreatic cancer through cGAS-STING pathway mediated immune regulation mechanism, columnId=1207314218647392369, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Original Article, runingTitle=null, highlight=null, articleAbstract=
AIM

To investigate the impact of erianin on the development of pancreatic cancer by regulating cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signal pathway.

METHODS

SW1990 cells were divided into control group, low-, medium- and high-concentration erianin groups (10, 20, 40 nmol·L-1), RU.521 (cGAS inhibitor)group (1 μmol·L-1), and erianin (40 nmol·L-1) +RU.521 (1 μmol·L-1) group. The proliferation was detected by CCK-8 method, and apoptosis was detected by flow cytometry. The migration and invasion of SW1990 cells were detected by scratch test and Transwell test, respectively. Western blot was applied to detect the protein expressions of cyclin D1, Bcl-2 associated X protein (Bax), matrix metalloproteinase (MMP)-2, MMP-9, cGAS and STING in SW1990 cells. SW1990 cells were co-cultured with NK cells for 48 hours, the levels of granzyme B and perforin (PF) in co-culture supernatant were detected by ELISA, and NK cell killing activity was detected.

RESULTS

Compared with the control group, the cell proliferation rate,the rate of scratch healing, the number of invasive cells were decreased in the low-, medium- and high-concentration erianin groups, the protein expressions of cyclin D1, MMP-2, MMP-9 were decreased, the apoptosis rate was increased, and the protein expressions of Bax, cGAS and STING were decreased in a concentration-dependent manner (P<0.05), while the change trends of the above indexes in the RU.521 group were opposite (P<0.05). Compared with the high-concentration erianin group, the cell proliferation rate, scratch healing rate, the number of invasive cells, and the protein expressions of cyclin D1,MMP-2, MMP-9, Bax, cGAS and STING in the erianin +RU.521 group were increased, and the apoptosis rate was decreased (P<0.05). In the co-culture experiment, compared with the control group, the levels of granzyme B and PF and NK cell killing activity in the cell supernatant of the low-, medium- and high-concentration erianin groups were increased in a concentration-dependent manner (P<0.05), while the change trends of corresponding indexes in the RU.521 group were opposite (P<0.05).Compared with the high-concentration erianin group, the levels of granzyme B and PF and NK cell killing activity in the erianin+RU.521 group were decreased (P<0.05).

CONCLUSION

Erianin may inhibit the proliferation, migration, invasion,and immune escape of pancreatic cancer cells and promote cell apoptosis by activating cGAS-STING signaling pathway.

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目的

探讨毛兰素调节环GMP-AMP合成酶（cGAS）-干扰素基因刺激因子（STING）信号通路对胰腺癌发生发展的影响。

方法

将人胰腺癌细胞系SW1990细胞分为对照组，毛兰素低、中、高浓度（10、20、40 nmol·L-1）组，RU.521（cGAS抑制剂，1 μmol·L-1）组，毛兰素（40 nmol·L-1）+RU.521（1 μmol·L-1）组。CCK-8法检测SW1990细胞增殖，流式细胞术检测细胞凋亡，划痕实验和Transwell实验检测细胞迁移和侵袭，Western blot法检测细胞周期蛋白D1（cyclin D1） 、Bcl-2相关X蛋白（Bax）、基质金属蛋白酶（MMP）-2、MMP-9、cGAS和STING蛋白表达。SW1990细胞与自然杀伤（NK）细胞共培养48 h，ELISA法检测共培养上清中颗粒酶B （granzyme B）、穿孔素（PF）水平，检测NK细胞杀伤活力变化。

结果

与对照组比较，毛兰素低、中、高浓度组细胞增殖率、划痕愈合率和侵袭细胞数目减少，cyclin D1、MMP-2、MMP-9蛋白表达降低，细胞凋亡率升高，Bax、cGAS、STING蛋白表达降低，呈浓度依赖性（P<0.05）；而RU.521组上述指标变化趋势相反（P<0.05）。与毛兰素高浓度组相比，毛兰素+RU.521组细胞增殖率、划痕愈合率和侵袭细胞数目及cyclin D1、MMP-2、MMP-9、Bax、cGAS、STING蛋白表达增高，细胞凋亡率降低（P<0.05）。共培养实验中，与对照组比较，毛兰素低、中、高浓度组细胞上清中granzyme B、PF水平和NK细胞杀伤活力升高，且呈浓度依赖性（P<0.05），而RU.521组对应指标变化趋势相反（P<0.05）；与毛兰素高浓度组相比，毛兰素+RU.521组granzyme B、PF水平和NK细胞杀伤活力降低（P<0.05）。

结论

毛兰素可能通过激活cGAS-STING信号通路抑制胰腺癌细胞的增殖、迁移、侵袭及免疫逃逸，促进细胞凋亡。

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田霞
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陈巍，男，副主任医师，硕士，主要从事胆胰系统肿瘤机制的研究，E-mail:

田霞，女，主任医师，硕士，主要从事消化系统相关肿瘤机制的研究，E-mail:

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陈巍，男，副主任医师，硕士，主要从事胆胰系统肿瘤机制的研究，E-mail:

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田霞，女，主任医师，硕士，主要从事消化系统相关肿瘤机制的研究，E-mail:

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田霞，女，主任医师，硕士，主要从事消化系统相关肿瘤机制的研究，E-mail:

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Erianin, a novel dibenzyl compound in Dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis[J].Signal Transduct Target Ther, 2020, 5（1）: 51-61., articleTitle=Erianin, a novel dibenzyl compound in Dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis, refAbstract=null), Reference(id=1240719599533093115, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710435742216598, doi=null, pmid=null, pmcid=null, year=2021, volume=279, issue=1, pageStart=114399, pageEnd=114410, url=null, language=null, rfNumber=[9], rfOrder=8, authorNames=WANG Y, CHU F, LIN J, journalName=J Ethnopharmacol, refType=null, unstructuredReference=WANG Y, CHU F, LIN J, et al. 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J Ethnopharmacol, 2021,279（1）: 114399-114410., articleTitle=Erianin, the main active ingredient of Dendrobium chrysotoxum Lindl, inhibits precancerous lesions of gastric cancer （PLGC） through suppression of the HRAS-PI3K-AKT signaling pathway as revealed by network pharmacology and in vitro experimental verification, refAbstract=null), Reference(id=1240719599637950717, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710435742216598, doi=null, pmid=null, pmcid=null, year=2020, volume=48, issue=1, pageStart=183, pageEnd=200, url=null, language=null, rfNumber=[10], rfOrder=9, authorNames=CHEN YT, HSIEH MJ, CHEN PN, journalName=Am J Chin Med, refType=null, unstructuredReference=CHEN YT, HSIEH MJ, CHEN PN, et al. Erianin induces apoptosis and autophagy in oral squamous cell carcinoma cells[J]. 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A：对照组，B：毛兰素低浓度组，C：毛兰素中浓度组，D：毛兰素高浓度组，E：RU.521组，F：毛兰素+ RU.521组

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A：对照组，B：毛兰素低浓度组，C：毛兰素中浓度组，D：毛兰素高浓度组，E：RU.521组，F：毛兰素+ RU.521组

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A：对照组，B：毛兰素低浓度组，C：毛兰素中浓度组，D：毛兰素高浓度组，E：RU.521组，F：毛兰素+ RU.521组

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A：对照组，B：毛兰素低浓度组，C：毛兰素中浓度组，D：毛兰素高浓度组，E：RU.521组，F：毛兰素+ RU.521组

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组别增殖活力凋亡率/%划痕愈合率/%细胞侵袭数/个
对照0.96±0.088.93±0.5846.24±2.0767.75±2.76
毛兰素低浓度0.85±0.07b15.15±0.73b37.78±1.65b54.56±2.36b
毛兰素中浓度0.73±0.06beh29.28±1.51beh29.56±1.33beh41.42±1.88beh
毛兰素高浓度0.33±0.02be48.83±2.21be14.56±0.68be23.36±1.05be
RU.5211.21±0.11b3.78±0.29b59.98±2.77b78.86±3.34b
毛兰素+RU.5210.77±0.06h23.69±1.13h32.26±1.73h46.65±2.11h
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各组细胞增殖活力和凋亡率比较

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组别增殖活力凋亡率/%划痕愈合率/%细胞侵袭数/个
对照0.96±0.088.93±0.5846.24±2.0767.75±2.76
毛兰素低浓度0.85±0.07b15.15±0.73b37.78±1.65b54.56±2.36b
毛兰素中浓度0.73±0.06beh29.28±1.51beh29.56±1.33beh41.42±1.88beh
毛兰素高浓度0.33±0.02be48.83±2.21be14.56±0.68be23.36±1.05be
RU.5211.21±0.11b3.78±0.29b59.98±2.77b78.86±3.34b
毛兰素+RU.5210.77±0.06h23.69±1.13h32.26±1.73h46.65±2.11h
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组别granzyme B/ pg·mL-1PF/pg·mL-1NK细胞杀伤活力/%
对照1.86±0.141.28±0.1010.26±0.43
毛兰素低浓度3.73±0.15b2.23±0.14b18.83±0.92b
毛兰素中浓度5.96±0.24beh2.97±0.16beh29.96±1.59beh
毛兰素高浓度8.95±0.43be4.67±0.18be42.26±2.87be
RU.5210.88±0.07b0.63±0.06b4.54±0.26b
毛兰素+RU.5214.56±0.23h2.57±0.12h24.45±1.36h
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各组共培养细胞上清中granzyme B、穿孔素（PF）和自然杀伤（NK）细胞水平比较

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组别granzyme B/ pg·mL-1PF/pg·mL-1NK细胞杀伤活力/%
对照1.86±0.141.28±0.1010.26±0.43
毛兰素低浓度3.73±0.15b2.23±0.14b18.83±0.92b
毛兰素中浓度5.96±0.24beh2.97±0.16beh29.96±1.59beh
毛兰素高浓度8.95±0.43be4.67±0.18be42.26±2.87be
RU.5210.88±0.07b0.63±0.06b4.54±0.26b
毛兰素+RU.5214.56±0.23h2.57±0.12h24.45±1.36h
), ArticleFig(id=1240719598522265821, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710435742216598, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别cyclin D1BaxMMP-2MMP-9cGASSTING
对照1.67±0.180.23±0.021.33±0.121.13±0.110.36±0.030.21±0.01
毛兰素低浓度1.25±0.13b0.37±0.02b1.08±0.09b0.87±0.08b0.49±0.03b0.56±0.04b
毛兰素中浓度1.03±0.08beh0.49±0.04beh0.82±0.07beh0.69±0.06beh0.98±0.05beh0.73±0.06beh
毛兰素高浓度0.51±0.05be0.78±0.06be0.26±0.03be0.31±0.03be1.46±0.13be1.16±0.12be
RU.5212.26±0.19b0.12±0.01b1.66±0.13b1.36±0.11b0.22±0.02b0.13±0.01b
毛兰素+RU.5211.18±0.11h0.43±0.03h0.95±0.08h0.78±0.07h0.53±0.05h0.65±0.05h
), ArticleFig(id=1240719598597763297, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710435742216598, language=CN, label=表3, caption=

各组SW1990细胞中cyclin D1、Bax、MMP-2、MMP-9、cGAS、STING蛋白表达比较

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组别cyclin D1BaxMMP-2MMP-9cGASSTING
对照1.67±0.180.23±0.021.33±0.121.13±0.110.36±0.030.21±0.01
毛兰素低浓度1.25±0.13b0.37±0.02b1.08±0.09b0.87±0.08b0.49±0.03b0.56±0.04b
毛兰素中浓度1.03±0.08beh0.49±0.04beh0.82±0.07beh0.69±0.06beh0.98±0.05beh0.73±0.06beh
毛兰素高浓度0.51±0.05be0.78±0.06be0.26±0.03be0.31±0.03be1.46±0.13be1.16±0.12be
RU.5212.26±0.19b0.12±0.01b1.66±0.13b1.36±0.11b0.22±0.02b0.13±0.01b
毛兰素+RU.5211.18±0.11h0.43±0.03h0.95±0.08h0.78±0.07h0.53±0.05h0.65±0.05h
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毛兰素通过cGAS-STING通路介导的免疫调控机制对胰腺癌发生发展的影响
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陈巍 , 韩峥 , 黄莎莎 , 蔡一珊 , 郭芳 , 田霞
中国新药与临床杂志 | 论著 2024,43(10): 790-795
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中国新药与临床杂志 | 论著 2024, 43(10): 790-795
毛兰素通过cGAS-STING通路介导的免疫调控机制对胰腺癌发生发展的影响
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陈巍 , 韩峥, 黄莎莎, 蔡一珊, 郭芳, 田霞
作者信息
  • 武汉市第三医院 消化内科，湖北 武汉　430060

    • 陈巍，男，副主任医师，硕士，主要从事胆胰系统肿瘤机制的研究，E-mail:

    田霞，女，主任医师，硕士，主要从事消化系统相关肿瘤机制的研究，E-mail:

通讯作者:

田霞
Impact of erianin on occurrence and development of pancreatic cancer through cGAS-STING pathway mediated immune regulation mechanism
Wei CHEN , Zheng HAN, Sha-sha HUANG, Yi-shan CAI, Fang GUO, Xia TIAN
Affiliations
  • Department of Gastroenterology, the Third Hospital of Wuhan, Wuhan HUBEI 430060, China
出版时间: 2024-10-25 doi: 10.14109/j.cnki.xyylc.2024.10.11
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摘要
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目的

探讨毛兰素调节环GMP-AMP合成酶（cGAS）-干扰素基因刺激因子（STING）信号通路对胰腺癌发生发展的影响。

方法

将人胰腺癌细胞系SW1990细胞分为对照组，毛兰素低、中、高浓度（10、20、40 nmol·L-1）组，RU.521（cGAS抑制剂，1 μmol·L-1）组，毛兰素（40 nmol·L-1）+RU.521（1 μmol·L-1）组。CCK-8法检测SW1990细胞增殖，流式细胞术检测细胞凋亡，划痕实验和Transwell实验检测细胞迁移和侵袭，Western blot法检测细胞周期蛋白D1（cyclin D1） 、Bcl-2相关X蛋白（Bax）、基质金属蛋白酶（MMP）-2、MMP-9、cGAS和STING蛋白表达。SW1990细胞与自然杀伤（NK）细胞共培养48 h，ELISA法检测共培养上清中颗粒酶B （granzyme B）、穿孔素（PF）水平，检测NK细胞杀伤活力变化。

结果

与对照组比较，毛兰素低、中、高浓度组细胞增殖率、划痕愈合率和侵袭细胞数目减少，cyclin D1、MMP-2、MMP-9蛋白表达降低，细胞凋亡率升高，Bax、cGAS、STING蛋白表达降低，呈浓度依赖性（P<0.05）；而RU.521组上述指标变化趋势相反（P<0.05）。与毛兰素高浓度组相比，毛兰素+RU.521组细胞增殖率、划痕愈合率和侵袭细胞数目及cyclin D1、MMP-2、MMP-9、Bax、cGAS、STING蛋白表达增高，细胞凋亡率降低（P<0.05）。共培养实验中，与对照组比较，毛兰素低、中、高浓度组细胞上清中granzyme B、PF水平和NK细胞杀伤活力升高，且呈浓度依赖性（P<0.05），而RU.521组对应指标变化趋势相反（P<0.05）；与毛兰素高浓度组相比，毛兰素+RU.521组granzyme B、PF水平和NK细胞杀伤活力降低（P<0.05）。

结论

毛兰素可能通过激活cGAS-STING信号通路抑制胰腺癌细胞的增殖、迁移、侵袭及免疫逃逸，促进细胞凋亡。

毛兰素  /  胰腺肿瘤  /  细胞增殖  /  细胞迁移抑制  /  环GMP
AIM

To investigate the impact of erianin on the development of pancreatic cancer by regulating cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signal pathway.

METHODS

SW1990 cells were divided into control group, low-, medium- and high-concentration erianin groups (10, 20, 40 nmol·L-1), RU.521 (cGAS inhibitor)group (1 μmol·L-1), and erianin (40 nmol·L-1) +RU.521 (1 μmol·L-1) group. The proliferation was detected by CCK-8 method, and apoptosis was detected by flow cytometry. The migration and invasion of SW1990 cells were detected by scratch test and Transwell test, respectively. Western blot was applied to detect the protein expressions of cyclin D1, Bcl-2 associated X protein (Bax), matrix metalloproteinase (MMP)-2, MMP-9, cGAS and STING in SW1990 cells. SW1990 cells were co-cultured with NK cells for 48 hours, the levels of granzyme B and perforin (PF) in co-culture supernatant were detected by ELISA, and NK cell killing activity was detected.

RESULTS

Compared with the control group, the cell proliferation rate,the rate of scratch healing, the number of invasive cells were decreased in the low-, medium- and high-concentration erianin groups, the protein expressions of cyclin D1, MMP-2, MMP-9 were decreased, the apoptosis rate was increased, and the protein expressions of Bax, cGAS and STING were decreased in a concentration-dependent manner (P<0.05), while the change trends of the above indexes in the RU.521 group were opposite (P<0.05). Compared with the high-concentration erianin group, the cell proliferation rate, scratch healing rate, the number of invasive cells, and the protein expressions of cyclin D1,MMP-2, MMP-9, Bax, cGAS and STING in the erianin +RU.521 group were increased, and the apoptosis rate was decreased (P<0.05). In the co-culture experiment, compared with the control group, the levels of granzyme B and PF and NK cell killing activity in the cell supernatant of the low-, medium- and high-concentration erianin groups were increased in a concentration-dependent manner (P<0.05), while the change trends of corresponding indexes in the RU.521 group were opposite (P<0.05).Compared with the high-concentration erianin group, the levels of granzyme B and PF and NK cell killing activity in the erianin+RU.521 group were decreased (P<0.05).

CONCLUSION

Erianin may inhibit the proliferation, migration, invasion,and immune escape of pancreatic cancer cells and promote cell apoptosis by activating cGAS-STING signaling pathway.

erianin  /  pancreatic neoplasms  /  cell proliferation  /  cell migration inhibition  /  cyclic GMP
陈巍, 韩峥, 黄莎莎, 蔡一珊, 郭芳, 田霞. 毛兰素通过cGAS-STING通路介导的免疫调控机制对胰腺癌发生发展的影响. 中国新药与临床杂志, 2024 , 43 (10) : 790 -795 . DOI: 10.14109/j.cnki.xyylc.2024.10.11
Wei CHEN, Zheng HAN, Sha-sha HUANG, Yi-shan CAI, Fang GUO, Xia TIAN. Impact of erianin on occurrence and development of pancreatic cancer through cGAS-STING pathway mediated immune regulation mechanism[J]. Chinese Journal of New Drugs and Clinical Remedies, 2024 , 43 (10) : 790 -795 . DOI: 10.14109/j.cnki.xyylc.2024.10.11
正文
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胰腺癌是最致命和最具侵袭性的恶性肿瘤之一，由于早期转移、侵袭性、耐药性和免疫逃逸等特点，80%~85%的胰腺癌患者在初诊时已发生局部浸润和远处转移[1]。胰腺癌可以通过化疗、放疗和手术进行治疗，对于晚期胰腺癌，化疗仍然是唯一的治疗选择。然而，目前用于治疗胰腺癌的药物由于耐受性、基因突变等问题，疗效可能会下降[2, 3]。激活环GMP-AMP合成酶（cGAS）-干扰素基因刺激因子（STING）信号通路可抑制胰腺癌的发生发展[4]。毛兰素（erianin）是从石斛中分离得到的具有多种抗肿瘤活性的化合物之一，已有研究报道，毛兰素可抑制人结肠癌细胞增殖[5]。本研究主要探究毛兰素对胰腺癌细胞增殖、凋亡、迁移、侵袭及免疫逃逸的影响及其作用机制。
材料与方法
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药物、试剂和仪器
毛兰素（规格：20 mg，纯度≥98%，溶于DMSO制成相应浓度的溶液）购自北京伊塔生物科技有限公司，cGAS抑制剂RU.521购自美国MCE公司。CCK-8试剂盒购自上海广锐生物科技有限公司，Annexin V-FITC/PI细胞凋亡检测试剂盒购自上海锐赛生物科技（集团）有限公司，人颗粒酶B（granzyme B）、穿孔素（perforin，PF）ELISA试剂盒购自上海晶抗生物工程有限公司，兔源一抗细胞周期蛋白D1（cyclin D1）、Bcl-2相关X蛋白（Bax）、基质金属蛋白酶（MMP）-2、MMP-9、cGAS、STING、GAPDH、辣根过氧化物酶（HRP）标记的羊抗兔二抗均购自英国Abcam公司。BD FACSVerse流式细胞仪购自广州市东和仪器科技有限公司，Mulltiskan FC酶标仪购自赛默飞世尔仪器有限公司，DM1000光学显微镜购自上海维翰光电科技有限公司。
细胞培养与分组
人胰腺癌细胞系SW1990购自深圳市豪地华拓生物科技有限公司。人源自然杀伤（NK）细胞购自优利科（上海）生命科学有限公司。将SW1990细胞在补充有10%胎牛血清的RPMI-1640培养基中培养。取对数生长期的SW1990细胞，参考文献并结合前期预实验结果，将SW1990细胞分为对照组，毛兰素低、中、高浓度（10、20、40 nmol·L-1）组，RU.521（1 μmol·L-1）组，毛兰素（40 nmol·L-1）+RU.521（1 μmol·L-1）组[6, 7]。对照组不作任何处理，其余各组给予对应浓度药物处理48 h。
细胞增殖
采用CCK-8法。将SW1990细胞以每孔1×104个的密度接种到96孔板中，分组处理后，向每孔中加入CCK-8溶液10 μL，孵育2 h后，通过酶标仪测定各组SW1990细胞在450 nm处的吸光度（A）值。
细胞凋亡
采用流式细胞术。分组处理后，将各组细胞浓度调整为1×105个·mL-1，取细胞悬液100 μL，向细胞悬液中加入Annexin V-FITC和PI各5 μL，避光孵育30 min后，检测SW1990细胞凋亡情况。
细胞迁移
采用划痕实验检测。将SW1990细胞以每孔1×105个的密度接种于6孔板中，使用药物进行分组处理，当细胞达到90%汇合度时，用10 μL移液管尖端轻轻地划动细胞层，然后用无胎牛血清的培养基继续培养细胞。利用光学显微镜观察细胞在0、48 h的划痕宽度，并记录0 h的划痕宽度为W0，48 h的划痕宽度为W48，划痕愈合率（%）=（W0-W48）/W0×100%。
细胞侵袭
采用Transwell测定。各组细胞浓度调整为1×105个·mL-1，取细胞悬液100 μL置于预先涂有Matrigel基质胶的Transwell上室中，再加入含10% FBS的RPMI-1640培养基500 μL于Transwell下室中，孵育48 h后，将侵袭细胞经甲醛固定、0.5%结晶紫溶液染色后，利用光学显微镜观察细胞侵袭情况。
共培养实验
以SW1990为靶细胞，NK细胞为效应细胞，将SW1990细胞与NK细胞以10：1的比例加入96孔板中共培养4 h。收集各组共培养细胞上清液。采用ELISA法，严格按照试剂盒说明书操作步骤检测共培养细胞上清中granzyme B、PF水平。另设SW1990细胞单独培养、SW1990细胞在10 μL 30%TritonX-100溶液中培养和NK细胞单独培养对照。取上清液50 μL加入新的96孔板中，同时加入乳酸脱氢酶反应液50 μL孵育30 min，再加入终止液50 μL孵育1 h终止反应，利用酶标仪测量450 nm处的A值。NK细胞杀伤活力（%）=（A实验组-ASW1990细胞单独培养-ANK细胞单独培养）/（ASW1990细胞在TritonX-100溶液中培养-A SW1990细胞单独培养）×100%。
cyclin D1、Bax、MMP-2、MMP-9、cGAS、STING蛋白表达
采用Western blot法。预冷的RIPA裂解缓冲液用于提取SW1990细胞总蛋白质，将蛋白质进行定量、电泳、转膜、封闭后，加入一抗cyclin D1（1：1 000）、Bax（1：1 000）、MMP-2（1：1 000）、MMP-9（1：1 000）、cGAS（1：1 000）、STING（1：2 000）、GAPDH（1：2 000）在4 ℃下孵育过夜。次日，加入羊抗兔二抗（1：2 000）在室温下孵育1.5 h。利用ECL试剂检测蛋白质条带的显色情况，Image J软件分析蛋白质条带的灰度值。
统计学分析
采用SPSS25.0版软件进行统计分析，符合正态分布且方差齐的数据用均值±标准差（）表示，多组间的差异比较采用单因素方差分析，进一步两两比较采用SNK-q检验，P<0.05表示有显著差异。
结果
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细胞增殖和凋亡
与对照组相比，毛兰素低、中、高浓度组细胞增殖活力显著降低，细胞凋亡率升高，且呈浓度依赖性（P<0.05）；RU.521组细胞增殖活力升高，细胞凋亡率降低（P<0.05）。与毛兰素高浓度组相比，毛兰素+RU.521组细胞增殖活力升高，细胞凋亡率降低（P<0.05）。见表1、图1。
细胞迁移能力
与对照组相比，毛兰素低、中、高浓度组细胞划痕愈合率降低，呈浓度依赖性（P<0.05）；RU.521组细胞划痕愈合率升高（P<0.05）。与毛兰素高浓度组相比，毛兰素+RU.521组细胞划痕愈合率升高（P<0.05）。见表1、图2。
细胞侵袭能力
与对照组比较，毛兰素低、中、高浓度组细胞侵袭数降低，呈浓度依赖性（P<0.05）；RU.521组细胞侵袭数升高（P<0.05）。与毛兰素高浓度组比较，毛兰素+RU.521组细胞侵袭数升高（P<0.05）。见表1、图3。
granzyme B、PF水平
与对照组相比，毛兰素低、中、高浓度组共培养细胞上清中granzyme B、PF水平升高，呈浓度依赖性（P<0.05）；RU.521组共培养细胞上清中granzyme B、PF水平降低（P<0.05）。与毛兰素高浓度组比较，毛兰素+RU.521组共培养细胞上清中granzyme B、PF水平降低（P<0.05）。见表2。
NK细胞杀伤活力的影响
与对照组相比，毛兰素低、中、高浓度组NK细胞杀伤活力升高，呈浓度依赖性（P<0.05）；RU.521组中NK细胞杀伤活力降低（P<0.05）。与毛兰素高浓度组组比较，毛兰素+RU.521共培养组中NK细胞杀伤活力降低（P<0.05）。见表2。
cyclin D1、Bax、MMP-2、MMP-9蛋白及cGAS-STING通路相关蛋白表达
与对照组比较，毛兰素低、中、高浓度组cyclin D1、MMP-2、MMP-9蛋白表达降低，Bax、cGAS、STING蛋白表达升高，呈浓度依赖性（P<0.05）；RU.521组cyclin D1、MMP-2、MMP-9蛋白表达升高，Bax、cGAS、STING蛋白表达降低（P<0.05）。与毛兰素高浓度组比较，毛兰素+RU.521组cyclin D1、MMP-2、MMP-9蛋白表达升高，Bax、cGAS、STING蛋白表达降低（P<0.05）。见图4和表3。
讨论
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毛兰素是一种从石斛中分离出来的天然产物，近年来其在癌症治疗中越来越受到关注。据报道，毛兰素可抑制肺癌细胞生长和迁移[8]、抑制胃癌癌前病变[9]、诱导口腔鳞状细胞癌细胞凋亡[10]；毛兰素恢复了细胞毒性T淋巴细胞杀死宫颈癌细胞的能力[11]。以上研究表明了毛兰素具有调控肿瘤细胞增殖、凋亡、迁移及免疫逃逸的作用。cyclin D1是一种可缩短细胞周期、加速细胞增殖的分子标志物[12]；Bax的表达水平与细胞凋亡能力成正比[13]；MMP-2、MMP-9是一组能够裂解细胞外基质成分的酶，它们具有促进细胞迁移与侵袭的能力[14]。本研究显示，毛兰素可抑制SW1990细胞中cyclin D1、MMP-2、MMP-9蛋白表达，降低细胞增殖能力、划痕愈合率和侵袭细胞数目，促进Bax蛋白表达，上调细胞凋亡率，且呈浓度依赖性，表明毛兰素可抑制SW1990细胞增殖、迁移与侵袭，促进细胞凋亡。此外，有研究表明，免疫逃逸参与了胰腺癌的恶性进展，且与胰腺癌的不良预后密切相关[15]；NK细胞作为免疫系统重要的组成部分，其可通过分泌granzyme B、PF等毒性因子发挥免疫监视进而清除肿瘤细胞[16]。本研究显示，毛兰素可呈浓度依赖性地促进共培养上清中granzyme B、PF表达，并增强共培养体系中NK细胞杀伤活力，表明毛兰素可抑制SW1990细胞免疫逃逸，提示毛兰素可能成为治疗胰腺癌的潜在有效药物。
cGAS-STING信号通路在抗肿瘤免疫中起着重要作用，是一个潜在的抗癌免疫治疗药物靶点[17]。据报道，激活非小细胞肺癌中的cGAS-STING信号通路可促进NK细胞浸润和抗肿瘤免疫[18]；激活cGAS-STING通路抑制了胃癌细胞增殖、迁移和免疫逃逸[19]。为了验证该推测，本研究加入cGAS抑制剂RU.521干预SW1990细胞，结果显示，与对照组比较，RU.521组SW1990细胞中cGAS、STING蛋白表达降低，SW1990细胞增殖、迁移、侵袭及免疫逃逸能力增强，细胞凋亡能力减弱，表明cGAS-STING通路确实参与了SW1990细胞增殖、迁移、侵袭、免疫逃逸及凋亡过程。毛兰素可浓度依赖性地上调SW1990细胞中cGAS、STING蛋白表达，而RU.521减弱了高剂量毛兰素对SW1990细胞增殖、迁移、侵袭、免疫逃逸的抑制作用，提示毛兰素可能通过激活cGAS-STING通路抑制SW1990细胞增殖、迁移、侵袭及免疫逃逸，促进细胞凋亡。
综上所述，毛兰素可能通过激活cGAS-STING通路抑制SW1990细胞增殖、迁移、侵袭及免疫逃逸，促进细胞凋亡。未进行体内实验进一步验证结论是本研究的不足之一，后期将会进一步深入探究。
基金
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  • 湖北省卫生健康委员会科研项目(WJ2023M129)
文献
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参考文献 引证文献
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2024年第43卷第10期
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doi: 10.14109/j.cnki.xyylc.2024.10.11
  • 接收时间：2023-03-13
  • 首发时间：2026-03-17
  • 出版时间：2024-10-25
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  • 收稿日期：2023-03-13
  • 录用日期：2024-06-02
基金
湖北省卫生健康委员会科研项目(WJ2023M129)
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    武汉市第三医院 消化内科，湖北 武汉　430060

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田霞
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2种不同金属材料的力学参数
科
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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