CircSMARCA5通过miR-4295/PTEN轴调控糖酵解抑制胃癌细胞增殖和侵袭

蔡娟; 陈志强; 左学良

doi:10.19401/j.cnki.1007-3639.2022.04.002

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CircSMARCA5通过miR-4295/PTEN轴调控糖酵解抑制胃癌细胞增殖和侵袭

论著 | 更新时间：2025-12-31

- CircSMARCA5通过miR-4295/PTEN轴调控糖酵解抑制胃癌细胞增殖和侵袭
- CircSMARCA5 inhibits glycolysis and suppresses proliferation and invasion of gastric cancer cells through miR-4295/PTEN axis
- 中国癌症杂志 2022年32卷第4期页码：298-308
- 作者机构：
  
  1. 皖南医学院第一附属医院（弋矶山医院）肿瘤内科,重大疾病非编码RNA转化研究安徽普通高校重点实验室,安徽芜湖 241001
  2. 南京医科大学第一附属医院肝胆中心,江苏南京 210029
  3. 皖南医学院第一附属医院（弋矶山医院）胃肠外科,安徽芜湖 241001
- 作者简介：
  
  [ "蔡娟（ORCID: https://orcid.org/0000-0001-7996-2525）,博士,主治医师 E-mail: caijuan1987@yeah.net" ]
  左学良（ORCID: https://orcid.org/0000-0001-5204-2585）,博士,副教授 E-mail: zuoxueliang0202@126.com
- 基金信息：
  
  国家自然科学基金(82103293);国家自然科学基金(82172651);国家自然科学基金(82002556);安徽省自然科学基金(1908085QH332);安徽省自然科学基金(2108085MH287);安徽省重点研究与开发计划(202104j07020019);安徽省高校优秀青年人才支持计划(gxyq2021257);皖南医学院弋矶山医院科研能力“高峰”培育计划(GF2019J08);皖南医学院弋矶山医院科研能力“高峰”培育计划(GF2019G17)
- DOI：10.19401/j.cnki.1007-3639.2022.04.002
  中图分类号： R735.2
- 收稿：2021-11-20，
  
  修回：2022-03-01，
  
  纸质出版：2022-04-30
- 稿件说明：
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蔡娟, 陈志强, 左学良. CircSMARCA5通过miR-4295/PTEN轴调控糖酵解抑制胃癌细胞增殖和侵袭[J]. 中国癌症杂志, 2022,32(4):298-308.

Juan CAI, Zhiqiang CHEN, Xueliang ZUO. CircSMARCA5 inhibits glycolysis and suppresses proliferation and invasion of gastric cancer cells through miR-4295/PTEN axis[J]. China Oncology, 2022, 32(4): 298-308.
蔡娟, 陈志强, 左学良. CircSMARCA5通过miR-4295/PTEN轴调控糖酵解抑制胃癌细胞增殖和侵袭[J]. 中国癌症杂志, 2022,32(4):298-308. DOI： 10.19401/j.cnki.1007-3639.2022.04.002.

Juan CAI, Zhiqiang CHEN, Xueliang ZUO. CircSMARCA5 inhibits glycolysis and suppresses proliferation and invasion of gastric cancer cells through miR-4295/PTEN axis[J]. China Oncology, 2022, 32(4): 298-308. DOI： 10.19401/j.cnki.1007-3639.2022.04.002.

摘要

背景与目的：

胃癌是常见的消化系统恶性肿瘤。作者既往研究发现circSMARCA5在胃癌中表达降低并能够抑制胃癌进展

但其具体机制目前仍不清楚。本研究探究circSMARCA5抑制胃癌细胞增殖和侵袭的分子机制。

方法：

采用细胞计数试剂盒-8（cell counting kit-8

CCK-8）和transwell实验检测过表达circSMARCA5对胃癌细胞增殖和侵袭能力的影响。通过检测细胞外酸化率、葡萄糖摄取水平和乳酸生成量

分析过表达circSMARCA5对胃癌细胞糖酵解的影响。采用实时荧光定量聚合酶链式反应（real-time fluorescent quantitative polymerase chain reaction

RTFQ-PCR）检测circSMARCA5、miR-4295和

PTEN

的基因表达

采用蛋白质印迹法（Western blot）检测GLUT1和LDHA的蛋白水平。建立BACB/c裸小鼠皮下移植瘤模型

观察过表达circSMARCA5对移植瘤生长的影响

利用免疫组织化学方法检测两组皮下瘤中GLUT1、LDHA的表达水平及Ki-67增殖指数。通过双荧光素酶报告基因实验、Pearson相关性分析和RNA免疫沉淀（RNA immunoprecipitation

RIP）实验检测circSMARCA5与miR-4295、miR-4295及PTEN的靶向调控关系。

结果：

过表达circSMARCA5能够抑制胃癌细胞增殖和侵袭。CircSMARCA5过表达组细胞的糖酵解速率、糖酵解能力值、葡萄糖摄取水平和乳酸生成量均低于对照组。此外

过表达circSMARCA5能够抑制裸小鼠皮下移植瘤的生长。进一步研究发现

circSMARCA5可发挥分子海绵作用下调miR-4295表达

而miR-4295通过与PTEN mRNA的3

#x02032;-UTR结合抑制PTEN表达。在circSMARCA5过表达组细胞中上调miR-4295或下调PTEN表达可部分逆转circSMARCA5对胃癌细胞增殖、侵袭和糖酵解的影响。

结论：

CircSMARCA5通过竞争性结合miR-4295上调PTEN表达

调控细胞糖酵解

从而抑制胃癌细胞的增殖和侵袭。

Abstract

Background and purpose:

Gastric cancer is one of the most common malignant tumors of digestive system. Previous study demonstrated that circSMARCA5 was downregulated and could function as a tumor suppressor in gastric cancer. However

the molecular mechanism has not yet been documented. This study aimed to investigate the effects of circSMARCA5 on the proliferation and invasion of gastric cancer cells and their molecular mechanisms.

Methods:

Cell counting kit-8 (CCK-8) assays and tr

answell assays were performed to examine the cell proliferative and invasive abilities

respectively. The effect of circSMARCA5 on gastric cancer cell glycolysis was assessed by detecting the extracellular acidification rate

glucose uptake level and lactate production. Real-time fluorescent quantitative polymerase chain reaction (RTFQ-PCR) assay was performed to detect the expression levels of circSMARCA5

miR-4295 and PTEN. The levels of GLUT1 and LDHA were measured by Western blot assay. The transplanted xenograft model in nude mice was established

and the effects of circSMARCA5 on the tumor growth were observed. Immunohistochemistry assays were performed to examine the expression levels of GLUT1

LDHA and Ki-67 proliferation index in xenograft tumors. Dual luciferase reporter gene assays

Pearson's correlation analysis and RNA immunoprecipitation (RIP) assays were used to confirm the targeting relationship of circSMARCA5 and miR-4295 as well as miR-4295 and PTEN.

Results:

CircSMARCA5 overexpression inhibited the proliferation and invasion of gastric cancer cells. Compared to the control group

the glycolysis rate

glycolysis capacity

glucose uptake and lactate production in the circSMARCA5-overexpresing group were significantly decreased. In addition

nude mouse transplanted xenograft assays showed that the volume and the weight of the tumors in the circSMARCA5-overexpressing group were lower compared with the control group. Further studies indicated that circSMARCA5 acted as a molecular sponge to inhibit the expression of miR-4295. Besides

miR-4295 could inhibit the expression of PTEN by binding with the 3'-UTR of PTEN mRNA. Rescue experiments by upregulating miR-4295 or downregulating PTEN expression in the circSMARCA5-overexpressing gastric cancer cells were performed

and the results showed that upregulation of miR-4295 or PTEN knockdown could abolish the inhibitory effects of circSMARCA5 overexpression on cell proliferation

invasion and glycolysis.

Conclusion:

CircSMARCA5 su

ppresses the proliferation and invasion of gastric cancer cells by targeting miR-4295

increasing the expression level of PTEN and subsequently regulating glycolysis.

关键词

Keywords

references

SUNG H , FERLAY J , SIEGEL R L , et al . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J ] . CA Cancer J Clin , 2021 , 71 ( 3 ): 209 - 249 . DOI: 10.3322/caac.21660 http://doi.org/10.3322/caac.21660 https://onlinelibrary.wiley.com/doi/10.3322/caac.21660 https://onlinelibrary.wiley.com/doi/10.3322/caac.21660

KIM E , KIM Y K , LEE S J V . Emerging functions of circular RNA in aging [J ] . Trends Genet , 2021 , 37 ( 9 ): 819 - 829 . DOI: 10.1016/j.tig.2021.04.014 http://doi.org/10.1016/j.tig.2021.04.014 https://linkinghub.elsevier.com/retrieve/pii/S0168952521001268 https://linkinghub.elsevier.com/retrieve/pii/S0168952521001268

LU J , WANG Y H , YOON C , et al . Circular RNA circ-RanGAP1 regulates VEGFA expression by targeting miR-877-3p to facilitate gastric cancer invasion and metastasis [J ] . Cancer Lett , 2020 , 471 : 38 - 48 . DOI: 10.1016/j.canlet.2019.11.038 http://doi.org/10.1016/j.canlet.2019.11.038 https://linkinghub.elsevier.com/retrieve/pii/S0304383519306020 https://linkinghub.elsevier.com/retrieve/pii/S0304383519306020

LI J F , HUANG C C , ZOU Y F , et al. CircTLK1 promotes the proliferation and metastasis of renal cell carcinoma by sponging miR-136-5p [J ] . Mol Cancer , 2020 , 19 ( 1 ): 103 . DOI: 10.1186/s12943-020-01225-2 http://doi.org/10.1186/s12943-020-01225-2 https://doi.org/10.1186/s12943-020-01225-2 https://doi.org/10.1186/s12943-020-01225-2

CAI J , CHEN Z Q , ZUO X L . circSMARCA 5 functions as a diagnostic and prognostic biomarker for gastric cancer [J ] . Dis Markers , 2019 , 2019 : 2473652 .

YU T , WANG Y F , FAN Y , et al . CircRNAs in cancer metabolism: a review [J ] . J Hematol Oncol , 2019 , 12 ( 1 ): 90 . DOI: 10.1186/s13045-019-0776-8 http://doi.org/10.1186/s13045-019-0776-8 https://doi.org/10.1186/s13045-019-0776-8 https://doi.org/10.1186/s13045-019-0776-8

LI J , SUN D , PU W C , et al . Circular RNAs in cancer: biogenesis, function, and clinical significance [J ] . Trends Cancer , 2020 , 6 ( 4 ): 319 - 336 . DOI: 10.1016/j.trecan.2020.01.012 http://doi.org/10.1016/j.trecan.2020.01.012 https://linkinghub.elsevier.com/retrieve/pii/S2405803320300285 https://linkinghub.elsevier.com/retrieve/pii/S2405803320300285

HE A T , LIU J L , LI F Y , et al . Targeting circular RNAs as a therapeutic approach: current strategies and challenges [J ] . Signal Transduct Target Ther , 2021 , 6 ( 1 ): 185 . DOI: 10.1038/s41392-021-00569-5 http://doi.org/10.1038/s41392-021-00569-5 https://doi.org/10.1038/s41392-021-00569-5 https://doi.org/10.1038/s41392-021-00569-5

WANG S M , ZHANG K , TAN S Y , et al . Circular RNAs in body fluids as cancer biomarkers: the new frontier of liquid biopsies [J ] . Mol Cancer , 2021 , 20 ( 1 ): 13 . DOI: 10.1186/s12943-020-01298-z http://doi.org/10.1186/s12943-020-01298-z https://doi.org/10.1186/s12943-020-01298-z https://doi.org/10.1186/s12943-020-01298-z

BEILERLI A , GAREEV I , BEYLERLI O , et al . Circular RNAs as biomarkers and therapeutic targets in cancer [J ] . Semin Cancer Biol , 2021: S1044-S579X ( 21 ) 00004 - 3 .

YU J , XU Q G , WANG Z G , et al . Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma [J ] . J Hepatol , 2018 , 68 ( 6 ): 1214 - 1227 . DOI: 10.1016/j.jhep.2018.01.012 http://doi.org/10.1016/j.jhep.2018.01.012 https://linkinghub.elsevier.com/retrieve/pii/S0168827818300552 https://linkinghub.elsevier.com/retrieve/pii/S0168827818300552

BARBAGALLO D , CAPONNETTO A , CIRNIGLIARO M , et al. CircSMARCA 5 inhibits migration of glioblastoma multiforme cells by regulating a molecular axis involving splicing factors SRSF1/SRSF3/PTB [J ] . Int J Mol Sci , 2018 , 19 ( 2 ): E480 .

VANDER HEIDEN M G , CANTLEY L C , THOMPSON C B . Understanding the Warburg effect: the metabolic requirements of cell proliferation [J ] . Science , 2009 , 324 ( 5930 ): 1029 - 1033 . DOI: 10.1126/science.1160809 http://doi.org/10.1126/science.1160809 https://www.science.org/doi/10.1126/science.1160809 https://www.science.org/doi/10.1126/science.1160809

EL HASSOUNI B , GRANCHI C , VALLÉS-MARTÍ A , et al . The dichotomous role of the glycolytic metabolism pathway in cancer metastasis: interplay with the complex tumor microenvironment and novel therapeutic strategies [J ] . Semin Cancer Biol , 2020 , 60 : 238 - 248 . DOI: 10.1016/j.semcancer.2019.08.025 http://doi.org/10.1016/j.semcancer.2019.08.025 https://linkinghub.elsevier.com/retrieve/pii/S1044579X19301804 https://linkinghub.elsevier.com/retrieve/pii/S1044579X19301804

MENG F Y , WU L , DONG L , et al. EGFL9 promotes breast cancer metastasis by inducing cMET activation and metabolic reprogramming [J ] . Nat Commun , 2019 , 10 ( 1 ): 5033 . DOI: 10.1038/s41467-019-13034-3 http://doi.org/10.1038/s41467-019-13034-3 https://doi.org/10.1038/s41467-019-13034-3 https://doi.org/10.1038/s41467-019-13034-3

PU Z C , XU M D , YUAN X L , et al . Circular RNA circCUL3 accelerates the Warburg effect progression of gastric cancer through regulating the STAT3/HK2 axis [J ] . Mol Ther Nucleic Acids , 2020 , 22 : 310 - 318 . DOI: 10.1016/j.omtn.2020.08.023 http://doi.org/10.1016/j.omtn.2020.08.023 https://linkinghub.elsevier.com/retrieve/pii/S2162253120302523 https://linkinghub.elsevier.com/retrieve/pii/S2162253120302523

YUAN Q G , ZHANG Y , LI J H , et al . High expression of microRNA-4295 contributes to cell proliferation and invasion of pancreatic ductal adenocarcinoma by the down-regulation of glypican-5 [J ] . Biochem Biophys Res Commun , 2018 , 497 ( 1 ): 73 - 79 . DOI: 10.1016/j.bbrc.2018.02.023 http://doi.org/10.1016/j.bbrc.2018.02.023 https://linkinghub.elsevier.com/retrieve/pii/S0006291X18302468 https://linkinghub.elsevier.com/retrieve/pii/S0006291X18302468

NAN Y H , WANG J , WANG Y , et al . Erratum: miR-4295 promotes cell growth in bladder cancer by targeting BTG1 [J ] . Am J Transl Res , 2017 , 9 ( 4 ): 1960 .

YAN R , LI K , YUAN D W , et al . Downregulation of microRNA-4295 enhances cisplatin-induced gastric cancer cell apoptosis through the EGFR/PI3K/Akt signaling pathway by targeting LRIG1 [J ] . Int J Oncol , 2018 , 53 ( 6 ): 2566 - 2578 .

YAN X B , WANG T , WANG J . Circ_0016760 acts as a sponge of microRNA-4295 to enhance E2F transcription factor 3 expression and facilitates cell proliferation and glycolysis in non-small cell lung cancer [J ] . Cancer Biother Radiopharm , 2022 , 37 ( 2 ): 147 - 158 . DOI: 10.1089/cbr.2020.3621 http://doi.org/10.1089/cbr.2020.3621 https://www.liebertpub.com/doi/10.1089/cbr.2020.3621 https://www.liebertpub.com/doi/10.1089/cbr.2020.3621

CHEN C Y , CHEN J Y , HE L N , et al . PTEN: tumor suppressor and metabolic regulator [J ] . Front Endocrinol (Lausanne) , 2018 , 9 : 338 . DOI: 10.3389/fendo.2018.00338 http://doi.org/10.3389/fendo.2018.00338 https://www.frontiersin.org/article/10.3389/fendo.2018.00338/full https://www.frontiersin.org/article/10.3389/fendo.2018.00338/full

ORTEGA-MOLINA A , SERRANO M . PTEN in cancer, metabolism, and aging [J ] . Trends Endocrinol Metab , 2013 , 24 ( 4 ): 184 - 189 . DOI: 10.1016/j.tem.2012.11.002 http://doi.org/10.1016/j.tem.2012.11.002 https://linkinghub.elsevier.com/retrieve/pii/S1043276012002020 https://linkinghub.elsevier.com/retrieve/pii/S1043276012002020

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