miR-325-3p Reduces Proliferation and Promotes Apoptosis of Gastric Cancer Cells by Inhibiting Human Antigen R
Zhengwei Huang
Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China wzhospital.cn
The Affiliated Kangning Hospital of Wenzhou Medical University, Zhejiang Provincial Clinical Research Center for Mental Disorder, Wenzhou, China
Search for more papers by this authorYacan Luo
Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China wzhospital.cn
Search for more papers by this authorCongcong Chen
The Affiliated Kangning Hospital of Wenzhou Medical University, Zhejiang Provincial Clinical Research Center for Mental Disorder, Wenzhou, China
Search for more papers by this authorChaoyang Zhou
Intensive Care Unit, The People’s Hospital of Yuhuan, Yuhuan, China
Search for more papers by this authorZhengkang Su
The Affiliated Kangning Hospital of Wenzhou Medical University, Zhejiang Provincial Clinical Research Center for Mental Disorder, Wenzhou, China
Search for more papers by this authorChang Cai
Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China wzhospital.cn
Search for more papers by this authorCorresponding Author
Xi Li
The Affiliated Kangning Hospital of Wenzhou Medical University, Zhejiang Provincial Clinical Research Center for Mental Disorder, Wenzhou, China
Search for more papers by this authorCorresponding Author
Wenzhi Wu
Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China wzhospital.cn
Search for more papers by this authorZhengwei Huang
Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China wzhospital.cn
The Affiliated Kangning Hospital of Wenzhou Medical University, Zhejiang Provincial Clinical Research Center for Mental Disorder, Wenzhou, China
Search for more papers by this authorYacan Luo
Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China wzhospital.cn
Search for more papers by this authorCongcong Chen
The Affiliated Kangning Hospital of Wenzhou Medical University, Zhejiang Provincial Clinical Research Center for Mental Disorder, Wenzhou, China
Search for more papers by this authorChaoyang Zhou
Intensive Care Unit, The People’s Hospital of Yuhuan, Yuhuan, China
Search for more papers by this authorZhengkang Su
The Affiliated Kangning Hospital of Wenzhou Medical University, Zhejiang Provincial Clinical Research Center for Mental Disorder, Wenzhou, China
Search for more papers by this authorChang Cai
Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China wzhospital.cn
Search for more papers by this authorCorresponding Author
Xi Li
The Affiliated Kangning Hospital of Wenzhou Medical University, Zhejiang Provincial Clinical Research Center for Mental Disorder, Wenzhou, China
Search for more papers by this authorCorresponding Author
Wenzhi Wu
Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China wzhospital.cn
Search for more papers by this authorAbstract
Human antigen R (HuR), also known as ELAVL1, is a widely expressed RNA-binding protein (RBP) that has a significant impact on the development and advancement of tumors. Our previous study found that 5-fluorouracil (5-FU) may impede the proliferation and increase apoptosis in gastric cancer cells by reducing the nucleocytoplasmic shuttling of HuR. However, how posttranscriptional regulation influences HuR functions in gastric cancer remains to be elucidated. Here, we demonstrated that miR-325-3p has the potential to regulate the expression level of HuR by directly binding to its 3′UTR, which in turn led to a significant reduction in proliferation and an increase in apoptosis in gastric cancer cells. In addition, xenograft experiment showed that knockdown of HuR or overexpression of miR-325-3p group exhibited smaller tumor sizes after transplant of gastric cancer cells into zebrafish larvae. Thus, our findings offer new insights into the pathogenesis of gastric cancer and may potentially assist in identifying novel targets for drug therapy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Open Research
Data Availability
All data generated or analyzed during the study are included within the article.
References
- 1 Deng W., Jin L., Zhuo H., Vasiliou V., and Zhang Y., Alcohol consumption and risk of stomach cancer: a meta-analysis, Chemico-Biological Interactions. (2021) 336, 109365, https://doi.org/10.1016/j.cbi.2021.109365.
- 2 Jin G., Lv J., Yang M., Wang M., Zhu M., Wang T., Yan C., Yu C., Ding Y., Li G., Ren C., Ni J., Zhang R., Guo Y., Bian Z., Zheng Y., Zhang N., Jiang Y., Chen J., Wang Y., Xu D., Zheng H., Yang L., Chen Y., Walters R., Millwood I. Y., Dai J., Ma H., Chen K., Chen Z., Hu Z., Wei Q., Shen H., and Li L., Genetic risk, incident gastric cancer, and healthy lifestyle: a meta-analysis of genome-wide association studies and prospective cohort study, The Lancet Oncology. (2020) 21, no. 10, 1378–1386, https://doi.org/10.1016/s1470-2045(20)30460-5.
- 3 Sung H., Ferlay J., Siegel R. L., Laversanne M., Soerjomataram I., Jemal A., and Bray F., Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA: A Cancer Journal for Clinicians. (2021) 71, no. 3, 209–249, https://doi.org/10.3322/caac.21660.
- 4 Smyth E. C., Nilsson M., Grabsch H. I., van Grieken N. C. T., and Lordick F., Gastric cancer, The Lancet. (2020) 396, 635–648, 10251, https://doi.org/10.1016/s0140-6736(20)31288-5.
- 5 Zhong Q., Chen Q. Y., Li P., Xie J. W., Wang J. B., Lin J. X., Lu J., Cao L. L., Lin M., Tu R. H., Zheng C. H., and Huang C. M., Prediction of conditional probability of survival after surgery for gastric cancer: a study based on eastern and western large data sets, Surgery. (2018) 163, no. 6, 1307–1316, https://doi.org/10.1016/j.surg.2018.02.011, 2-s2.0-85045891998.
- 6 de Silanes I. L., Zhan M., Lal A., Yang X., and Gorospe M., Identification of a target RNA motif for RNA-binding protein HuR, Proceedings of the National Academy of Sciences of the United States of America. (2004) 101, no. 9, 2987–2992, https://doi.org/10.1073/pnas.0306453101, 2-s2.0-1542297742.
- 7 Liu Y., Chen X., Cheng R., Yang F., Yu M., Wang C., Cui S., Hong Y., Liang H., Liu M., Zhao C., Ding M., Sun W., Liu Z., Sun F., Zhang C., Zhou Z., Jiang X., and Chen X., The Jun/miR-22/HuR regulatory axis contributes to tumourigenesis in colorectal cancer, Molecular Cancer. (2018) 17, no. 1, https://doi.org/10.1186/s12943-017-0751-3, 2-s2.0-85040715915.
- 8 Abdelmohsen K., Srikantan S., Kuwano Y., and Gorospe M., miR-519 reduces cell proliferation by lowering RNA-binding protein HuR levels, Proceedings of the National Academy of Sciences of the United States of America. (2008) 105, no. 51, 20297–20302, https://doi.org/10.1073/pnas.0809376106, 2-s2.0-58149511991.
- 9 Chen Y., Yang F., Fang E., Xiao W., Mei H., Li H., Li D., Song H., Wang J., Hong M., Wang X., Huang K., Zheng L., and Tong Q., Circular RNA circAGO2 drives cancer progression through facilitating HuR-repressed functions of AGO2-miRNA complexes, Cell Death & Differentiation. (2019) 26, no. 7, 1346–1364, https://doi.org/10.1038/s41418-018-0220-6, 2-s2.0-85055120783.
- 10
Yang F.,
Hu A.,
Li D.,
Wang J.,
Guo Y.,
Liu Y.,
Li H.,
Chen Y.,
Wang X.,
Huang K.,
Zheng L., and
Tong Q., Circ-HuR suppresses HuR expression and gastric cancer progression by inhibiting CNBP transactivation, Molecular Cancer. (2019) 18, no. 1, https://doi.org/10.1186/s12943-019-1094-z.
10.1186/s12943-019-1094-z Google Scholar
- 11 Li Q., Tong D., Guo C., Wu F., Li F., Wang X., Jiang Q., Wei Y., Liu L., Ni L., Guo B., and Huang C., MicroRNA-145 suppresses gastric cancer progression by targeting Hu-antigen R, American Journal of Physiology-Cell Physiology. (2020) 318, no. 3, C605–C614, https://doi.org/10.1152/ajpcell.00118.2019.
- 12 Goutas D., Pergaris A., Giaginis C., and Theocharis S., HuR as therapeutic target in cancer: what the future holds, Current Medicinal Chemistry. (2022) 29, no. 1, 56–65, https://doi.org/10.2174/0929867328666210628143430.
- 13 Zhang Z., Huang A., Zhang A., and Zhou C., HuR promotes breast cancer cell proliferation and survival via binding to CDK3 mRNA, Biomedicine & Pharmacotherapy. (2017) 91, 788–795, https://doi.org/10.1016/j.biopha.2017.04.063, 2-s2.0-85019101215.
- 14
Ahmed R.,
Muralidharan R.,
Srivastava A.,
Johnston S. E.,
Zhao Y. D.,
Ekmekcioglu S.,
Munshi A., and
Ramesh R., Molecular targeting of HuR oncoprotein suppresses MITF and induces apoptosis in melanoma cells, Cancers. (2021) 13, no. 2, https://doi.org/10.3390/cancers13020166.
10.3390/cancers13020166 Google Scholar
- 15 Kakuguchi W., Kitamura T., Kuroshima T., Ishikawa M., Kitagawa Y., Totsuka Y., Shindoh M., and Higashino F., HuR knockdown changes the oncogenic potential of oral cancer cells, Molecular Cancer Research. (2010) 8, no. 4, 520–528, https://doi.org/10.1158/1541-7786.mcr-09-0367, 2-s2.0-77951155303.
- 16 Giammanco A., Blanc V., Montenegro G., Klos C., Xie Y., Kennedy S., Luo J., Chang S. H., Hla T., Nalbantoglu I., Dharmarajan S., and Davidson N. O., Intestinal epithelial HuR modulates distinct pathways of proliferation and apoptosis and attenuates small intestinal and colonic tumor development, Cancer Research. (2014) 74, no. 18, 5322–5335, https://doi.org/10.1158/0008-5472.can-14-0726, 2-s2.0-84907546688.
- 17 Assoni G., La Pietra V., Digilio R., Ciani C., Licata N. V., Micaelli M., Facen E., Tomaszewska W., Cerofolini L., Perez-Rafols A., Varela Rey M., Fragai M., Woodhoo A., Marinelli L., Arosio D., Bonomo I., Provenzani A., and Seneci P., HuR-targeted agents: an insight into medicinal chemistry, biophysical, computational studies and pharmacological effects on cancer models, Advanced Drug Delivery Reviews. (2022) 181, 114088, https://doi.org/10.1016/j.addr.2021.114088.
- 18 Filippova N., Yang X., Ananthan S., Calano J., Pathak V., Bratton L., Vekariya R. H., Zhang S., Ofori E., Hayward E. N., Namkoong D., Crossman D. K., Crowley M. R., King P. H., Mobley J., and Nabors L. B., Targeting the HuR oncogenic role with a new class of cytoplasmic dimerization inhibitors, Cancer Research. (2021) 81, no. 8, 2220–2233, https://doi.org/10.1158/0008-5472.can-20-2858.
- 19
Singh G. and
Storey K. B., MicroRNA cues from nature: a roadmap to decipher and combat challenges in human Health and disease?, Cells. (2021) 10, no. 12, https://doi.org/10.3390/cells10123374.
10.3390/cells10123374 Google Scholar
- 20 Wang S., Wang Z., Wang Q., Cui Y., and Luo S., Clinical significance of the expression of miRNA-21, miRNA-31 and miRNA-let7 in patients with lung cancer, Saudi Journal of Biological Sciences. (2019) 26, no. 4, 777–781, https://doi.org/10.1016/j.sjbs.2018.12.009, 2-s2.0-85060848683.
- 21
Hill M. and
Tran N., miRNA interplay: mechanisms and consequences in cancer, Disease Models & Mechanisms. (2021) 14, no. 4, 047662, https://doi.org/10.1242/dmm.047662.
10.1242/dmm.047662 Google Scholar
- 22 Rupaimoole R. and Slack F. J., MicroRNA therapeutics: towards a new era for the management of cancer and other diseases, Nature Reviews Drug Discovery. (2017) 16, no. 3, 203–222, https://doi.org/10.1038/nrd.2016.246, 2-s2.0-85013059434.
- 23 Sun T., Li K., Zhu K., Yan R., Dang C., and Yuan D., SNHG6 interacted with miR-325-3p to regulate cisplatin resistance of gastric cancer by targeting GITR<, OncoTargets and Therapy. (2020) 13, 12181–12193, https://doi.org/10.2147/ott.s262896.
- 24 Yao S., Zhao T., and Jin H., Expression of MicroRNA-325-3p and its potential functions by targeting HMGB1 in non-small cell lung cancer, Biomedicine & Pharmacotherapy. (2015) 70, 72–79, https://doi.org/10.1016/j.biopha.2015.01.013, 2-s2.0-84927520862.
- 25 Gan H., Lin L., Hu N., Yang Y., Gao Y., Pei Y., Chen K., and Sun B., KIF2C exerts an oncogenic role in nonsmall cell lung cancer and is negatively regulated by miR-325-3p, Cell Biochemistry and Function. (2019) 37, no. 6, 424–431, https://doi.org/10.1002/cbf.3420, 2-s2.0-85069936414.
- 26 Li L., Ji Y., Chen Y. C., and Zhen Z. J., MiR-325-3p mediate the CXCL17/CXCR8 axis to regulate angiogenesis in hepatocellular carcinoma, Cytokine. (2021) 141, 155436, https://doi.org/10.1016/j.cyto.2021.155436.
- 27 Westerfield M., The zebrafish book: a guide for the laboratory use of zebrafish (Danio rerio), The Zebrafish Book: A Guide for the Laboratory Use of Zebrafish (Danio rerio). (2007) University of Oregon Press, Portland, OR, USA.
- 28 Wu W., Xu S., Guan K., Zhang W., Chen C., Chen X., Hong Z., and Hua D., 5-FU blocks shuttling of HuR mediated by PKCδ in gastric cancer cells, Translational Cancer Research. (2020) 9, no. 8, 4790–4799, https://doi.org/10.21037/tcr-20-2129.
- 29 Lv J., Zhang S., Liu Y., Li C., Guo T., Zhang S., Li Z., Jiao Z., Sun H., Zhang Y., and Xu L., NR2F1-AS1/miR-190a/PHLDB2 induces the epithelial-mesenchymal transformation process in gastric cancer by promoting phosphorylation of AKT3, Frontiers in Cell and Developmental Biology. (2021) 9, 688949, https://doi.org/10.3389/fcell.2021.688949.
- 30
Wu J. Q.,
Zhai J.,
Li C. Y.,
Tan A. M.,
Wei P.,
Shen L. Z., and
He M. F., Patient-derived xenograft in zebrafish embryos: a new platform for translational research in gastric cancer, Journal of Experimental & Clinical Cancer Research. (2017) 36, no. 1, https://doi.org/10.1186/s13046-017-0631-0, 2-s2.0-85034583731.
10.1186/s13046-017-0631-0 Google Scholar
- 31 Wu X. and Xu L., The RNA-binding protein HuR in human cancer: a friend or foe?, Advanced Drug Delivery Reviews. (2022) 184, 114179, https://doi.org/10.1016/j.addr.2022.114179.
- 32
Wu X.,
Gardashova G.,
Lan L.,
Han S.,
Zhong C.,
Marquez R. T.,
Wei L.,
Wood S.,
Roy S.,
Gowthaman R.,
Karanicolas J.,
Gao F. P.,
Dixon D. A.,
Welch D. R.,
Li L.,
Ji M.,
Aube J., and
Xu L., Targeting the interaction between RNA-binding protein HuR and FOXQ1 suppresses breast cancer invasion and metastasis, Communications Biology. (2020) 3, no. 1, https://doi.org/10.1038/s42003-020-0933-1.
10.1038/s42003-020-0933-1 Google Scholar
- 33 Lal S., Cheung E. C., Zarei M., Preet R., Chand S. N., Mambelli-Lisboa N. C., Romeo C., Stout M. C., Londin E., Goetz A., Lowder C. Y., Nevler A., Yeo C. J., Campbell P. M., Winter J. M., Dixon D. A., and Brody J. R., CRISPR knockout of the HuR gene causes a xenograft lethal phenotype, Molecular Cancer Research. (2017) 15, no. 6, 696–707, https://doi.org/10.1158/1541-7786.mcr-16-0361, 2-s2.0-85020384006.
- 34 Meisner N. C., Hintersteiner M., Mueller K., Bauer R., Seifert J. M., Naegeli H. U., Ottl J., Oberer L., Guenat C., Moss S., Harrer N., Woisetschlaeger M., Buehler C., Uhl V., and Auer M., Identification and mechanistic characterization of low-molecular-weight inhibitors for HuR, Nature Chemical Biology. (2007) 3, no. 8, 508–515, https://doi.org/10.1038/nchembio.2007.14, 2-s2.0-34447532192.
- 35 Manzoni L., Zucal C., Maio D. D., D′Agostino V. G., Thongon N., Bonomo I., Lal P., Miceli M., Baj V., Brambilla M., Cerofolini L., Elezgarai S., Biasini E., Luchinat C., Novellino E., Fragai M., Marinelli L., Provenzani A., and Seneci P., Interfering with HuR-RNA interaction: design, synthesis and biological characterization of tanshinone mimics as novel, effective HuR inhibitors, Journal of Medicinal Chemistry. (2018) 61, no. 4, 1483–1498, https://doi.org/10.1021/acs.jmedchem.7b01176, 2-s2.0-85042585457.
- 36 Snaar-Jagalska B. E. and Zf-Cancer, ZF-CANCER: developing high-throughput bioassays for human cancers in zebrafish, Zebrafish. (2009) 6, no. 4, 441–443, https://doi.org/10.1089/zeb.2009.0614, 2-s2.0-74049141347.