Alternative Splicing of Cyr61 Is Regulated by Hypoxia and Significantly Changed in Breast Cancer
Abstract
Hypoxia is known to induce the transcriptional activation of pathways involved in angiogenesis, growth factor signaling, and tissue invasion and is therefore a potential key regulator of tumor growth. Cyr61 (cysteine rich 61) is a secreted, matricellular protein with proangiogenic capabilities and is transcriptionally induced under hypoxic conditions. High expression levels of Cyr61 were already detected in various cancer types and linked to tumor progression and advanced stages in breast cancer. Besides hypoxia, there is some evidence that posttranscriptional pre-mRNA processing could be involved in the regulation of Cyr61 expression, but was thus far not investigated. We studied the expression pattern of Cyr61 mRNA and protein in breast cancer cell lines as well as in matched pairs of noncancerous breast tissue, preinvasive lesions, and invasive breast cancers, respectively. In addition, we analyzed the potential regulatory capability of hypoxia on Cyr61 expression by functional tissue culture experiments. Our study revealed a stage-dependent induction of Cyr61 mRNA and protein in breast cancer tumorigenesis and for the first time alternative splicing of the Cyr61 gene due to intron retention. Breast carcinogenesis was accompanied by a shift from an intron 3 retaining toward an intron 3 skipping mRNA phenotype consecutively leading to processing of the biological active Cyr61 protein. The functional analyses strongly emphasize that hypoxia serves as a specific inducer of alternative Cyr61 splicing toward the intron skipping mRNA isoform with potential biological consequences in tumor cells. [Cancer Res 2009;69(5):2082–90]
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Another alternative splicing event retains intron 3, resulting in two stop codons that would terminate CCN1 within the central hinge region; this splicing is blocked under hypoxia in breast cancer cells, leading to full-length CCN1.
“Another alternative splicing event retains intron 3, resulting in two stop codons that would terminate the CCN1 polypeptide within the central hinge region. However, this alternative splicing is blocked under hypoxic conditions in breast cancer cells, leading to the synthesis of full-length CCN1 [48].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [48]
Cites
Hypoxia — a key regulatory factor in tumour growth
Harris, A. L. (2002) · Nature Reviews Cancer · doi:10.1038/nrc704 · Cited by 5,177 · see citing works
Mechanisms of Alternative Pre-Messenger RNA Splicing
Black, D. L. (2003) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.72.121801.161720 · Cited by 2,704 · see citing works
Understanding alternative splicing: towards a cellular code
Matlin, A. J., Clark, F., & Smith, C. W. J. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1645 · Cited by 1,299 · see citing works
Alternative Splicing: New Insights from Global Analyses
Blencowe, B. J. (2006) · Cell · doi:10.1016/j.cell.2006.06.023 · Cited by 1,122 · see citing works
CCN proteins: multifunctional signalling regulators
Perbal, B. (2004) · The Lancet · doi:10.1016/s0140-6736(03)15172-0 · Cited by 704 · see citing works
All in the CCN family: essential matricellular signaling modulators emerge from the bunker
Leask, A., & Abraham, D. (2006) · Journal of Cell Science · doi:10.1242/jcs.03270 · Cited by 653 · see citing works
The CCN Family of Angiogenic Regulators: The Integrin Connection
Lau, L. F., & Lam, S. C.-T. (1999) · Experimental Cell Research · doi:10.1006/excr.1999.4456 · Cited by 645 · see citing works
Aberrant and Alternative Splicing in Cancer
Venables, J. P. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1910 · Cited by 630 · see citing works
Peer Bork, B. (1993) · FEBS Letters · doi:10.1016/0014-5793(93)80155-n · Cited by 623 · see citing works
The Connective Tissue Growth Factor/Cysteine- Rich 61/Nephroblastoma Overexpressed (CCN) Family
Brigstock, D. R. (1999) · Endocrine Reviews · doi:10.1210/edrv.20.2.0360 · Cited by 588 · see citing works
Protein Diversity from Alternative Splicing
Black, D. L. (2000) · Cell · doi:10.1016/s0092-8674(00)00128-8 · Cited by 565 · see citing works
Burd, C. G., & Dreyfuss, G. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06369.x · Cited by 488 · see citing works
A quantitative analysis of intron effects on mammalian gene expression
Nott, A., MEISLIN, S. H., & Moore, M. J. (2003) · RNA · doi:10.1261/rna.5250403 · Cited by 417 · see citing works
The Connective Tissue Growth Factor/Cysteine- Rich 61/Nephroblastoma Overexpressed (CCN) Family
Brigstock, D. R. (1999) · Endocrine Reviews · doi:10.1210/er.20.2.189 · Cited by 370 · see citing works
NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues
Perbal, B. (2001) · Molecular Pathology · doi:10.1136/mp.54.2.57 · Cited by 345 · see citing works
Kireeva, M. L., Mo, F.-E., Yang, G. P., & Lau, L. F. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.4.1326 · Cited by 341 · see citing works
The evolving roles of alternative splicing
Lareau, L. F., Green, R. E., Bhatnagar, R. S., & Brenner, S. E. (2004) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2004.05.002 · Cited by 315 · see citing works
Expression of cyr61, a growth factor-inducible immediate-early gene.
O'Brien, T. P., Yang, G. P., Sanders, L., & Lau, L. F. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.7.3569 · Cited by 310 · see citing works
Brigstock, D. R. (2002) · Angiogenesis · doi:10.1023/a:1023823803510 · Cited by 300 · see citing works
Si, W., Kang, Q., Luu, H. H., Park, J. K., Luo, Q., Song, W.-X., Jiang, W., Luo, X., Li, X., Yin, H., et al. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.8.2955-2964.2006 · Cited by 272 · see citing works
Alternative splicing: an emerging topic in molecular and clinical oncology
Pajares, M. J., Ezponda, T., Catena, R., Calvo, A., Pı́o, R., & Montuenga, L. M. (2007) · The Lancet Oncology · doi:10.1016/s1470-2045(07)70104-3 · Cited by 261 · see citing works
Leu, S.-J., Lam, S. C.-T., & Lau, L. F. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m209288200 · Cited by 247 · see citing works
Kireeva, M. L., Latinkic, B., Kolesnikova, T. V., Chen, C.-C., Yang, G. P., Abler, A. S., & Lau, L. F. (1997) · Experimental Cell Research · doi:10.1006/excr.1997.3548 · Cited by 236 · see citing works
Detection and evaluation of intron retention events in the human transcriptome
Galante, P. A. F., Sakabe, N. J., Kirschbaum-Slager, N., & SOUZA, S. J. D. (2004) · RNA · doi:10.1261/rna.5123504 · Cited by 228 · see citing works
Alternative splicing in cancer: Noise, functional, or systematic?
Skotheim, R. I., & Nees, M. (2007) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2007.02.016 · Cited by 208 · see citing works
Stickeler, E., Fraser, S. D., Honig, A., Chen, A. L., Berget, S. M., & Cooper, T. A. (2001) · The EMBO Journal · doi:10.1093/emboj/20.14.3821 · Cited by 196 · see citing works
Self-citationLin, M.-T., Chang, C.-C., Chen, S.-T., Chang, H.-L., Su, J.-L., Chau, Y.-P., & Kuo, M.-L. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402305200 · Cited by 194 · see citing works
Molecular responses to hypoxia in tumor cells.
Kunz, M., & Ibrahim, S. M. (2003) · Molecular Cancer · doi:10.1186/1476-4598-2-23 · Cited by 192 · see citing works
Cyr61 promotes breast tumorigenesis and cancer progression
Tsai, M.-S., Bogart, D. F., Castañeda, J. M., Li, P., & Lupu, R. (2002) · Oncogene · doi:10.1038/sj.onc.1205682 · Cited by 189 · see citing works
Yang, G. P., & Lau, L. F. (1991) · PubMed · Cited by 187 · see citing works
Xie, D., Yin, D., Wang, H., Liu, G., Elashoff, R. M., Black, K. L., & Koeffler, H. P. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-0659-03 · Cited by 179 · see citing works
Stage-specific changes in SR splicing factors and alternative splicing in mammary tumorigenesis
Stickeler, E., Kittrell, F. S., Medina, D., & Berget, S. M. (1999) · Oncogene · doi:10.1038/sj.onc.1202671 · Cited by 175 · see citing works
Self-citationFunctional properties and intracellular signaling of CCN1/Cyr61
Chen, Y., & Du, X. (2006) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21194 · Cited by 167 · see citing works
Sequence features responsible for intron retention in human
Sakabe, N. J., & de Souza, S. (2007) · BMC Genomics · doi:10.1186/1471-2164-8-59 · Cited by 164 · see citing works
An Alternative-Exon Database and Its Statistical Analysis
Stamm, S., Zhu, J., Nakai, K., Stoilov, P., Stoß, O., & Zhang, M. Q. (2000) · DNA and Cell Biology · doi:10.1089/104454900750058107 · Cited by 156 · see citing works
The Yeast hnRNP-like Protein Hrp1/Nab4 Marks a Transcript for Nonsense-Mediated mRNA Decay
Gonzalez, C. I., Ruiz-Echevarría, M. J., Vasudevan, S., Henry, M. F., & Peltz, S. W. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80443-8 · Cited by 155 · see citing works
Menendez, J. A., Vellon, L., Mehmi, I., Teng, P. K., Griggs, D. W., & Lupu, R. (2005) · Oncogene · doi:10.1038/sj.onc.1208238 · Cited by 154 · see citing works
Watermann, D. O., Tang, Y., Hausen, A. Z., Jäger, M., Stamm, S., & Stickeler, E. (2006) · Cancer Research · doi:10.1158/0008-5472.can-04-3294 · Cited by 128 · see citing works
Self-citationAbé, M., & Sato, Y. (2001) · Angiogenesis · doi:10.1023/a:1016018617152 · Cited by 123 · see citing works
The angiogenic factor CYR61 in breast cancer: molecular pathology and therapeutic perspectives.
Men√©ndez, J. A., Mehmi, I., Griggs, D. W., & Lupu, R. (2003) · Endocrine Related Cancer · doi:10.1677/erc.0.0100141 · Cited by 120 · see citing works
Mechanisms of Hypoxic Gene Regulation of Angiogenesis Factor Cyr61 in Melanoma Cells
Kunz, M., Moeller, S., Koczan, D., Lorenz, P., Wenger, R. H., Glocker, M. O., Thiesen, H.-J., Gross, G., & Ibrahim, S. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301373200 · Cited by 104 · see citing works
CCN proteins and cancer: two to tango
Bleau, A. (2005) · Frontiers in bioscience · doi:10.2741/1594 · Cited by 97 · see citing works
Sampath, D., Winneker, R. C., & Zhang, Z. (2001) · Endocrinology · doi:10.1210/endo.142.6.8186 · Cited by 97 · see citing works
Cyr61, a deregulated gene in endometriosis
Absenger, Y. (2004) · Molecular Human Reproduction · doi:10.1093/molehr/gah053 · Cited by 95 · see citing works
Daoud, R., Mies, G., Smialowska, A., Oláh, L., Hossmann, K.-A., & Stamm, S. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-14-05889.2002 · Cited by 89 · see citing works
Structural genomics analysis of alternative splicing and application to isoform structure modeling
Wang, P., Yan, B., Guo, J., Hicks, C., & Xu, Y. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506770102 · Cited by 67 · see citing works
Hammacher, A., Thompson, E. W., & Williams, E. D. (2004) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.07.011 · Cited by 49 · see citing works
Functional domains of CCN1 (Cyr61) regulate breast cancer progression
O’Kelly, J., Chung, A. P., Lemp, N. A., Chumakova, K., Yin, D., Wang, H., SAID, J. W., Gui, D., Miller, C. W., Karlan, B. Y., et al. (2008) · International Journal of Oncology · doi:10.3892/ijo.33.1.59 · Cited by 49 · see citing works
Chromosomal mapping and expression of the human cyr61 gene in tumour cells from the nervous system.
Martinerie, C., Viégas-Pèquignot, E., Nguyen, V. C., & Perbal, B. (1997) · Molecular Pathology · doi:10.1136/mp.50.6.310 · Cited by 26 · see citing works
Sampath, D., Winneker, R. C., & Zhang, Z. (2002) · Endocrine · doi:10.1385/endo:18:2:147 · Cited by 25 · see citing works
Stickeler, E., Möbus, V. J., Kieback, D., Kohlberger, P., Runnebaum, I., & Kreienberg, R. (1997) · PubMed · Cited by 12 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Function of alternative splicing
Stamm, S., Ben‐Ari, S., Rafalska, I., Tang, Y., Zhang, Z., Toiber, D., Thanaraj, T. A., & Soreq, H. (2004) · Gene · doi:10.1016/j.gene.2004.10.022 · Cited by 1,373 · see citing works
Function of alternative splicing
Kelemen, O., Convertini, P., Zhang, Z., Wen, Y., Shen, M., Falaleeva, M., & Stamm, S. (2013) · Gene · doi:10.1016/j.gene.2012.07.083 · Cited by 743 · see citing works
Detained introns are a novel, widespread class of post-transcriptionally spliced intronsPreprint
Boutz, P. L., Bhutkar, A. J., & Sharp, P. A. (2015) · Genes & Development · doi:10.1101/gad.247361.114 · Cited by 414 · see citing works
CCN1/CYR61: the very model of a modern matricellular protein
Lau, L. F. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0778-3 · Cited by 338 · see citing works
Site identification in high-throughput RNA–protein interaction data
Uren, P. J., Bahrami‐Samani, E., Burns, S. C., Qiao, M., Karginov, F. V., Hodges, E. C., Hannon, G. J., Sanford, J. R., Penalva, L. O. F., & Smith, A. D. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts569 · Cited by 324 · see citing works
Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer
Farina, A. R., Cappabianca, L. A., Sebastiano, M., Zelli, V., Guadagni, S., & Mackay, A. R. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01616-9 · Cited by 131 · see citing works
Emerging role of CCN family proteins in tumorigenesis and cancer metastasis (Review)
Li, J., Ye, L., Owen, S., Weeks, H. P., Zhang, Z., & Jiang, W. G. (2015) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2015.2390 · Cited by 120 · see citing works
miR-205 Expression Promotes Cell Proliferation and Migration of Human Cervical Cancer Cells
Xie, H. Y., Zhao, Y., Caramuta, S., Larsson, C., & Lui, W. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046990 · Cited by 117 · see citing works
Oncogenic Alternative Splicing Switches: Role in Cancer Progression and Prospects for Therapy
Bonomi, S., Gallo, S., Catillo, M., Pignataro, D. S., Biamonti, G., & Ghigna, C. (2013) · International Journal of Cell Biology · doi:10.1155/2013/962038 · Cited by 117 · see citing works
Klopfleisch, R., Lenze, D., Hummel, M., & Gruber, A. D. (2010) · BMC Cancer · doi:10.1186/1471-2407-10-618 · Cited by 109 · see citing works
Hypoxia-Induced Alternative Splicing in Endothelial Cells
Weigand, J. E., Boeckel, J., Gellert, P., & Dimmeler, S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042697 · Cited by 88 · see citing works
CCN proteins: A centralized communication network
Perbal, B. (2013) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-013-0193-7 · Cited by 90 · see citing works
Nonsense-mediated RNA decay and its bipolar function in cancer
Nogueira, G., Fernandes, R. O., García-Moreno, J. F., & Romão, L. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01364-0 · Cited by 89 · see citing works
The CCN proteins: important signaling mediators in stem cell differentiation and tumorigenesis.
Zuo, G., Kohls, C. D., He, B., Chen, L., Zhang, W., Shi, Q., Zhang, B. Q., Kang, Q., Luo, J., Luo, X., et al. (2010) · PubMed · doi:10.14670/hh-25.795 · Cited by 87 · see citing works
Nuclear retention of mRNAs – quality control, gene regulation and human disease
Wegener, M., & Müller-McNicoll, M. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.11.001 · Cited by 86 · see citing works
Perspective in Alternative Splicing Coupled to Nonsense-Mediated mRNA Decay
García-Moreno, J. F., & Romão, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249424 · Cited by 83 · see citing works
Hypoxia is a Key Driver of Alternative Splicing in Human Breast Cancer Cells
Han, J., Li, J., Ho, J. C., Chia, G. S., Kato, H., Jha, S., Yang, H. H., Poellinger, L., & Lee, K. L. (2017) · Scientific Reports · doi:10.1038/s41598-017-04333-0 · Cited by 78 · see citing works
The role of alternative splicing coupled to nonsense-mediated mRNA decay in human disease
da Costa, P. J., Menezes, J., & Romão, L. (2017) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2017.07.013 · Cited by 77 · see citing works
Akaike, Y., Masuda, K., Kuwano, Y., Nishida, K., Kajita, K., Kurokawa, K., Satake, Y., Shoda, K., Imoto, I., & Rokutan, K. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.00333-14 · Cited by 73 · see citing works
Sudemycin E influences alternative splicing and changes chromatin modifications
Convertini, P., Shen, M., Potter, P. M., Palacios, G. F., Lagisetti, C., de la Grange, P., Horbinski, C., Fondufe‐Mittendorf, Y. N., Webb, T. R., & Stamm, S. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku151 · Cited by 72 · see citing works
CCN1: a novel inflammation-regulated biphasic immune cell migration modulator
Löbel, M., Bauer, S., Meisel, C., Eisenreich, A., Kudernatsch, R., Tank, J., Rauch, U., Kühl, U., Schultheiß, H., Volk, H., et al. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-0981-x · Cited by 68 · see citing works
Hypoxia induces immunosuppression, metastasis and drug resistance in pancreatic cancers
Zhang, H., Cao, K., Xiang, J., Zhang, M., Zhu, M., & Xi, Q. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216345 · Cited by 67 · see citing works
Physiological and pathophysiological role of nonsense-mediated mRNA decay
Ottens, F., & Gehring, N. H. (2016) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-016-1826-5 · Cited by 61 · see citing works
Hypoxia Regulates Alternative Splicing of HIF and non-HIF Target Genes
Sena, J. A., Wang, L., Heasley, L. E., & Hu, C. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-14-0149 · Cited by 63 · see citing works
Increased Serine-Arginine (SR) Protein Phosphorylation Changes Pre-mRNA Splicing in Hypoxia
Jakubauskienė, E., Vilys, L., Makino, Y., Poellinger, L., & Kanopka, A. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.639690 · Cited by 55 · see citing works
Ahuja, N., Ashok, C., Natua, S., Pant, D., Cherian, A., Pandkar, M. R., Yadav, P., Vishnu Narayanan, S. S., Mishra, J., Samaiya, A., et al. (2020) · NAR Cancer · doi:10.1093/narcan/zcaa021 · Cited by 53 · see citing works
Post-transcriptional regulation in cancer progression
Jewer, M., Findlay, S. D., & Postovit, L.-M. M. (2012) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-012-0179-x · Cited by 51 · see citing works
Regulation of pro-angiogenic tissue factor expression in hypoxia-induced human lung cancer cells
Eisenreich, A., Zakrzewicz, A., Huber, K., THIERBACH, H., Pepke, W., Goldin-Lang, P., Schultheiß, H., Pries, A. R., & Rauch, U. (2013) · Oncology Reports · doi:10.3892/or.2013.2413 · Cited by 47 · see citing works
A novel anti-Cyr61 antibody inhibits breast cancer growth and metastasis in vivo
Lin, J., Huo, R., Wang, L., Zhou, Z., Sun, Y., Shen, B., Wang, R., & Li, N. (2011) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-011-1135-y · Cited by 47 · see citing works
Nordin, A., Larsson, E., Thornell, L., & Holmberg, M. (2010) · Human Genetics · doi:10.1007/s00439-010-0931-3 · Cited by 45 · see citing works
Wang, Y.-J., Yang, B., Lai, Q., Shi, J., Peng, J., Zhang, Y., Hu, K., Li, Y., Peng, J.-W., Yang, Z.-Z., et al. (2020) · RNA Biology · doi:10.1080/15476286.2020.1804697 · Cited by 45 · see citing works
Schedel, M., Frei, R., Bieli, C., Cameron, L., Adamski, J., Lauener, R. P., & Kabesch, M. (2009) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2009.06.024 · Cited by 40 · see citing works
Alternative splicing of CCN mRNAs …. it has been upon us
Perbal, B. (2009) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-009-0051-9 · Cited by 40 · see citing works
Balance between MAT2A intron detention and splicing is determined cotranscriptionally
Pendleton, K. E., Park, S.-K., Hunter, O. V., Bresson, S. M., & Conrad, N. K. (2018) · RNA · doi:10.1261/rna.064899.117 · Cited by 37 · see citing works
The Roles of CCN1/CYR61 in Pulmonary Diseases
Zhu, Y., Almuntashiri, S., Han, Y., Wang, X., Somanath, P. R., & Zhang, D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21217810 · Cited by 35 · see citing works
Maroni, P., Matteucci, E., Luzzati, A., Perrucchini, G. G., Bendinelli, P., & Desiderio, M. A. (2010) · Breast Cancer Research and Treatment · doi:10.1007/s10549-010-1240-1 · Cited by 36 · see citing works
CCN3 modulates bone turnover and is a novel regulator of skeletal metastasis
Ouellet, V., & Siegel, P. M. (2012) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-012-0161-7 · Cited by 36 · see citing works
Hypoxia-driven splicing into noncoding isoforms regulates the DNA damage response
Memon, D., Dawson, K., Smowton, C., Wei, X., Dive, C., & Miller, C. J. (2016) · npj Genomic Medicine · doi:10.1038/npjgenmed.2016.20 · Cited by 34 · see citing works
Yan, L., & Chaqour, B. (2013) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-013-0206-6 · Cited by 34 · see citing works
Pant, D., Narayanan, S. P., Vijay, N., & Shukla, S. (2020) · Journal of Biosciences · doi:10.1007/s12038-019-9977-0 · Cited by 32 · see citing works
Hirschfeld, M., Zhang, B., Jaeger, M., Stamm, S., Erbes, T., Mayer, S., Tong, X., & Stickeler, E. (2013) · Molecular Carcinogenesis · doi:10.1002/mc.22045 · Cited by 33 · see citing works
Self-citationAlternative Splicing-Related Factor YT521
Zhang, B., Hausen, A. Z., Orlowska‐Volk, M., Jäger, M., Bettendorf, H., Stamm, S., Hirschfeld, M., Yiqin, O., Tong, X., Gitsch, G., et al. (2010) · International Journal of Gynecological Cancer · doi:10.1111/igc.0b013e3181d66ffe · Cited by 28 · see citing works
Self-citationOuyang, Y. Q., Hausen, A. Z., Orlowska‐Volk, M., Jäger, M., Bettendorf, H., Hirschfeld, M., Tong, X. W., & Stickeler, E. (2010) · International Journal of Cancer · doi:10.1002/ijc.25544 · Cited by 26 · see citing works
Self-citationCell survival: Interplay between hypoxia and pre-mRNA splicing
Kanopka, A. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.03.018 · Cited by 26 · see citing works
Cote, G. J., Zhu, W., Thomas, A., Martin, E., Murad, F., & Sharina, I. G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041099 · Cited by 23 · see citing works
Use of patient derived urine renal epithelial cells to confirm pathogenicity of PKHD1 alleles
Molinari, E., Srivastava, S., Dewhurst, R. M., & Sayer, J. A. (2020) · BMC Nephrology · doi:10.1186/s12882-020-02094-z · Cited by 23 · see citing works
Hypoxia-induced alternative splicing in human diseases: the pledge, the turn, and the prestige
Natua, S., Ashok, C., & Shukla, S. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03727-0 · Cited by 22 · see citing works
CCN1 Suppresses Pulmonary Vascular Smooth Muscle Contraction in Response to Hypoxia
Lee, S., Zhang, M., Hu, K., Lin, L., Zhang, D., & Jin, Y. (2015) · Pulmonary Circulation · doi:10.1086/683812 · Cited by 21 · see citing works
Alternative Splicing and Hypoxia Puzzle in Alzheimer’s and Parkinson’s Diseases
Jakubauskienė, E., & Kanopka, A. (2021) · Genes · doi:10.3390/genes12081272 · Cited by 19 · see citing works
Cysteine-rich 61 (CYR61) is up-regulated in proliferative diabetic retinopathy
Zhang, X., Yu, W., & Dong, F.-T. (2011) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/s00417-011-1882-7 · Cited by 19 · see citing works
Spencer, C., Montalvo, J., McLaughlin, S. R., & Bryan, B. A. (2011) · PubMed · Cited by 19 · see citing works
Dysregulation of splicing variants and spliceosome components in breast cancer
Gahete, M. D., Hermán‐Sánchez, N., Fuentes-Fayos, A. C., Lopez-Canovas, J. L., & Luque, R. M. (2022) · Endocrine Related Cancer · doi:10.1530/erc-22-0019 · Cited by 19 · see citing works
Mesenchymal stem cell contact promotes CCN1 splicing and transcription in myeloma cells
Dotterweich, J., Ebert, R., Kraus, S., Tower, R. J., Jakob, F. J., & Schütze, N. (2014) · Cell Communication and Signaling · doi:10.1186/1478-811x-12-36 · Cited by 17 · see citing works
Expression of tumor-promoting Cyr61 is regulated by hTRA2- 1 and acidosis
Hirschfeld, M., Jaeger, M., Buratti, E., Stuani, C., Grueneisen, J. S., Gitsch, G., & Stickeler, E. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr128 · Cited by 16 · see citing works
Self-citationOxygen regulates molecular mechanisms of cancer progression and metastasis
Gupta, K., Madan, E., Sayyid, M. M., Arias‐Pulido, H., Moreno, E., Kuppusamy, P., & Gogna, R. (2013) · Cancer and Metastasis Reviews · doi:10.1007/s10555-013-9464-2 · Cited by 15 · see citing works
Leu, S.-J. J., Sung, J.-S., Huang, M.-L., Chen, M., & Tsai, T.-W. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.04.045 · Cited by 14 · see citing works
Mapping Extracellular Protein–Protein Interactions Using Extracellular Proximity Labeling (ePL)
Peeney, D., Gurung, S., Rich, J. A., Coates-Park, S., Liu, Y., Toor, J., Jones, J., Richie, C. T., Jenkins, L. M., & Stetler-Stevenson, W. G. (2024) · Journal of Proteome Research · doi:10.1021/acs.jproteome.4c00606 · Cited by 13 · see citing works
Insights into Muscle Degeneration from Heritable Inclusion Body Myopathies
Krause, S. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00013 · Cited by 13 · see citing works
Bartkowiak, K., Heidrich, I., Kwiatkowski, M., Gorges, T. M., Andreas, A., Geffken, M., Verpoort, K., Müller, V., Schlüter, H., & Pantel, K. (2021) · Cancers · doi:10.3390/cancers13030563 · Cited by 14 · see citing works
Investigating Microenvironmental Regulation of Human Chordoma Cell Behaviour
Patel, P., Brooks, C. R., Seneviratne, A. K., Hess, D. A., & Séguin, C. A. (2014) · PLoS ONE · doi:10.1371/journal.pone.0115909 · Cited by 11 · see citing works
Li, J., Ye, L., Sun, P., Zheng, F., Ruge, F., Satherley, L. K., Feng, Y., Zhao, H., Du, G., Wang, T., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.15439 · Cited by 10 · see citing works
Clinical relevance of Cyr61 expression in patients with hormone-dependent breast cancer
Mayer, S., Erbes, T., Timme‐Bronsert, S., Jaeger, M., Rücker, G., Kuf, F., Stickeler, E., Gitsch, G., & Hirschfeld, M. (2017) · Oncology Letters · doi:10.3892/ol.2017.6406 · Cited by 9 · see citing works
Self-citationU2AF - Hypoxia-induced fas alternative splicing regulator
Vilys, L., Pečiulienė, I., Jakubauskienė, E., Zinkevičiūtė, R., Makino, Y., & Kanopka, A. (2020) · Experimental Cell Research · doi:10.1016/j.yexcr.2020.112444 · Cited by 9 · see citing works
Nonsense-mediated mRNA decay: a key regulatory system engaged in cancer
Pan, H., Wu, X., Hu, B., Xiong, H., Luo, Y., & Zhou, J. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02503-6 · Cited by 8 · see citing works
Hypoxia-Associated Alternative Splicing Signature in Lung Adenocarcinoma
Xu, Z., Wei, J., Qin, F., Sun, Y., Xiang, W., Yuan, L., Qin, J., Deng, K., Zheng, T., & Li, S. (2020) · Epigenomics · doi:10.2217/epi-2020-0399 · Cited by 9 · see citing works
Alternative Splicing in Prostate and Breast Cancer
Watson, P. M., & Watson, D. K. (2010) · The Open Cancer Journal · doi:10.2174/1874079001003010062 · Cited by 8 · see citing works
Post-transcriptional Regulation of Gene Expression via Unproductive Splicing
Zavileyskiy, L. G., & Pervouchine, D. D. (2024) · Acta Naturae · doi:10.32607/actanaturae.27337 · Cited by 7 · see citing works
Salem, I. H., Kamoun, F. F., Louhichi, N., Rouis, S., Mziou, M., Fendri-Kriaa, N., Ayadi, F. M., Triki, C., & Fakhfakh, F. (2010) · Bioscience Reports · doi:10.1042/bsr20100026 · Cited by 7 · see citing works
Welch, M. D., Howlett, M., Halse, H. M., Greene, W. K., & Kees, U. R. (2015) · Leukemia Research · doi:10.1016/j.leukres.2015.05.008 · Cited by 6 · see citing works
Grassi, T. F., Bidinotto, L. T., Lopes, G. A. D., Zapaterini, J. R., Rodrigues, M. A. M., & Barbisan, L. F. (2018) · Nutrition Research · doi:10.1016/j.nutres.2018.09.009 · Cited by 6 · see citing works
Gauck, S., Schultheiß, H., Rauch, U., & Eisenreich, A. (2013) · Cardiovascular System · doi:10.7243/2052-4358-1-8 · Cited by 5 · see citing works
Ortiz-Hernández, G. L., Patrick, C. S., Hinz, S., LaBarge, M. A., Li, Y. R., & Neuhausen, S. L. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26188991 · Cited by 3 · see citing works
Resistance to antiangiogenic treatments: A review
Koltai, T., Reshkin, S. J., & Cardone, R. A. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-90190-1.00014-7 · Cited by 3 · see citing works
The Potential of Targeting Splicing for Cancer Therapy
Grosso, A. R., & Carmo‐Fonseca, M. (2013) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-1-4614-8039-6_13 · Cited by 3 · see citing works
Polymorphisms of the CYR61 gene in patients with acute myeloid leukemia in a Han Chinese population
Niu, C., Wan, Y., Yang, C., Li, T., & Liao, P. (2018) · Medicine · doi:10.1097/md.0000000000011963 · Cited by 2 · see citing works
What’s in an intron? CCN1 mRNA splicing in cancer
Leask, A. (2009) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-009-0050-x · Cited by 2 · see citing works
Alternative Splicing and Human Disease
Stamm, S. (2017) · Encyclopedia of Life Sciences · doi:10.1002/9780470015902.a0021435.pub2 · Cited by 2 · see citing works
Sutherland, R. L. (2009) · Breast Cancer Online · doi:10.1017/s1470903109990216
(2011) · Elsevier eBooks · doi:10.1016/b978-0-12-387819-9.00029-3
Li, Z. (2024) · American Journal of Cancer Research · doi:10.62347/ckmt4065
Molinari, E., Srivastava, S., Dewhurst, R. M., & Sayer, J. A. (2020) · Figshare · doi:10.6084/m9.figshare.13100986
The extended Split-ORF pipeline: Prediction and evaluation of Split-ORFs using Ribo-seq dataPreprint
Kalk, C., Murtagh, J., Despic, V., Müller-McNicoll, M., & Schulz, M. H. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.22.727176
Alternative splicing rewires breast cancer and opens therapeutic avenues
Jin, Y., Liang, Y., Kasvaei, M. M., & Yang, Q. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-026-03017-5 · Cited by 1 · see citing works
Matricellular Proteins in Bladder Cancer: Context-Dependent Roles in Tumor Promotion and Suppression
Akhmetkaliyev, A., García, J. H. G. F., Sonnenberg-Riethmacher, E., & Riethmacher, D. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27156807
Yu, S., Gong, X. Q., Yang, Y., Duan, Y., Zhang, S., Wang, Y., Wang, Z., Bi, C., & Sun, H. (2026) · Science Advances · doi:10.1126/sciadv.aea2001
- Authors
- Hirschfeld, M., zur Hausen, A., Bettendorf, H., Jäger, M., & Stickeler, E.
- Affiliations
- University Medical Center Freiburg (DE)
- 2Institute of Pathology, Freiburg University Medical Center, Freiburg, Germany
- Venue
- Cancer Research
- Published
- 2009-03-01
- Volume
- 69
- Issue
- 5
- Pages
- 2082-2090
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2021418778
- Cited by
- 86
- References
- 50
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 10 · 2018: 4 · 2017: 7 · 2016: 2 · 2015: 6 · 2014: 5 · 2013: 9 · 2012: 8
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- CYR61, alternative splicing, hypoxia, breast cancer, intron retention, matricellular proteins, angiogenesis, tumor progression, preinvasive breast lesions, tumor stage, post-transcriptional regulation
- MeSH terms
- Breast, Breast Neoplasms, Female, Humans, Immunohistochemistry, RNA, Messenger, Cell Hypoxia, Alternative Splicing, Cell Line, Tumor, Cysteine-Rich Protein 61
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