Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell

Yae, Toshifumi; Tsuchihashi, Kazufumi; Ishimoto, Takatsugu; Motohara, Takeshi; Yoshikawa, Masahide; Yoshida, Go J.; Wada, Toshimi; Masuko, Takashi; Mogushi, Kaoru; Tanaka, Hiroshi; Osawa, Tsuyoshi; Kanki, Yasuharu; Minami, Takashi; Aburatani, Hiroyuki; Ohmura, Mitsuyo; Kubo, Akiko; Suematsu, Makoto; Takahashi, Kazuhisa; Saya, Hideyuki; Nagano, Osamu

doi:10.1038/ncomms1892

Cited by 331 publications

(335 citation statements)

References 53 publications

(72 reference statements)

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“…Among the downregulated genes in treated tumors, were the metastasis-suppressor gene NDRG1 (23) and the adhesion molecule EPCAM, a regulator of the alternative splicing of CD44 (ESRP1; ref. 24) and ST14 (a negative regulator of the EMT mediator ZEB1; Table 2; Fig. 1A; ref.…”

Section: Differential Gene Expression Between Treated and Nontreatedmentioning

confidence: 99%

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

Marín-Aguilera

Codony-Servat

Reig

et al. 2014

Molecular Cancer Therapeutics

138

112

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Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel þ androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-kB transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44 þ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44 þ subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evidence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer. Mol Cancer Ther; 13(5); 1270-84. Ó2014 AACR.

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Section: Differential Gene Expression Between Treated and Nontreatedmentioning

confidence: 99%

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

Marín-Aguilera

Codony-Servat

Reig

et al. 2014

Molecular Cancer Therapeutics

138

112

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“…The overexpression of ESRP1 has been reported to cause a splicing switch from CD44s to CD44v (18)(19)(20). In order to examine the differential roles of CD44s and CD44v8-10 in bone metastases, the current study employed an approach in which the ESRP1 gene was stably transduced into MDA-MB-231 human breast cancer cells and A549 human lung cancer cells (MDA/ESRP1 and A549/ESRP1, respectively).…”

Section: Effects Of Esrp1 Overexpression On Bone Metastases Esrp1mentioning

confidence: 99%

“…is an epithelial-specific splicing factor that regulates the alternative splicing of several genes, including CD44 (18)(19)(20). The overexpression of ESRP1 has been reported to cause a splicing switch from CD44s to CD44v (18)(19)(20).…”

Section: Effects Of Esrp1 Overexpression On Bone Metastases Esrp1mentioning

confidence: 99%

Comparable roles of CD44v8-10 and CD44s in the development of bone metastases in a mouse model

Hiraga

Nakamura

2016

Oncology Letters

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Abstract. Cluster of differentiation (CD)44 has been implicated in cancer metastasis to bone. Clinical and experimental studies have suggested that the standard isoform of CD44 (CD44s) and the variant isoform of CD44 (CD44v) enhance metastasis. The present study examined the differential roles of CD44s and CD44v, particularly CD44v8-10, in the development of bone metastases. For this purpose, MDA-MB-231 human breast cancer cells and A549 human lung cancer cells were stably transduced with epithelial splicing regulatory protein 1 (ESRP1), which regulates the alternative splicing of several genes, including CD44. The introduction of ESRP1 induced a splicing switch from CD44s to CD44v, particularly to CD44v8-10, while the total amount of CD44 was rarely affected. However, ESRP1 did not significantly affect cell proliferation, migration, invasion or tumor sphere formation in vitro. Furthermore, ESRP1 did not cause significant differences in the development of bone metastases in a mouse model. As an alternative approach, cancer cells transduced with the CD44v8-10 gene were also established. The overexpression of CD44v8-10 in MCF-7 human breast cancer cells, which rarely express any isoform of CD44, promoted cell migration and sphere formation, whereas the overexpression of CD44v8-10 in MDA-MB-231 cells, which endogenously express high levels of CD44s, did not exert these effects.The results of the present study collectively suggest that the ability of CD44v8-10 to promote tumor aggressiveness and bone metastases is similar to that of CD44s. CD44v8-10 and CD44s may represent potential therapeutic targets for the treatment of bone metastases. IntroductionCluster of differentiation (CD)44 is a transmembrane glycoprotein that functions as an adhesion molecule for extracellular matrices, primarily hyaluronan (1,2). The expression of CD44 in cancer cells has also been implicated in cell migration, invasion and metastasis (1,2). Furthermore, CD44 has recently been recognized as a major marker for cancer stem cells (CSCs) in several types of cancer (2,3).The CD44 gene consists of 20 exons, 10 of which (exons 1-5 and 16-20) encode the shortest and ubiquitously expressed standard isoform of CD44 (CD44s) (1,2). The other 10 exons (exons 6-15, also referred to as exons v1-v10) are variant exons inserted by alternative splicing in various combinations, thereby generating various variant isoforms of CD44 (CD44v) (1,2). The insertion of variant exons lengthens the extracellular domain and alters the binding and signaling properties of CD44. The expression of CD44v is restricted to a few epithelial tissues, including several types of cancer (2). Although extensive research has been conducted, the association between the expression of CD44v and tumor aggressiveness remains controversial (1,2,4-6).CD44v8-10, also known as CD44R1 and CD44E, is one of the isoforms of CD44v, and contains the variant exons 13-15 (v8-v10) (1,2). Clinical studies have demonstrated that CD44v8-10 is expressed in various human epithelial cancers, including...

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“…Tissue specific alternative splicing is usually regulated by a combination of tissue-specific and ubiquitously expressed splicing factors (Pan et al, 2008;Sultan et al, 2008;Chen and Manley, 2009;Bland et al, 2010) and has been demonstrated to play an important role in regulation of tissue-specific protein interaction networks (Buljan et al, 2012). In addition, mis-regulated alternative RNA splicing events have a significant role in human diseases, cell cycle, and cell death (Hallegger et al, 2010;Gang et al, 2011;Honda et al, 2012;Raghavachari, 2012;Yae et al, 2012). For example, a specific isoform of pyruvate kinase resulting from hnRNP-mediated mRNA alternative splicing is required for tumor cell proliferation .…”

Section: Regulation Of Alternative Rna Splicingmentioning

confidence: 99%

Global impact of RNA splicing on transcriptome remodeling in the heart

Gao

Wang

2012

J. Zhejiang Univ. Sci. B

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In the eukaryotic transcriptome, both the numbers of genes and different RNA species produced by each gene contribute to the overall complexity. These RNA species are generated by the utilization of different transcriptional initiation or termination sites, or more commonly, from different messenger RNA (mRNA) splicing events. Among the 30 000+ genes in human genome, it is estimated that more than 95% of them can generate more than one gene product via alternative RNA splicing. The protein products generated from different RNA splicing variants can have different intracellular localization, activity, or tissue-distribution. Therefore, alternative RNA splicing is an important molecular process that contributes to the overall complexity of the genome and the functional specificity and diversity among different cell types. In this review, we will discuss current efforts to unravel the full complexity of the cardiac transcriptome using a deep-sequencing approach, and highlight the potential of this technology to uncover the global impact of RNA splicing on the transcriptome during development and diseases of the heart.

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Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell

Cited by 331 publications

References 53 publications

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

Comparable roles of CD44v8-10 and CD44s in the development of bone metastases in a mouse model

Global impact of RNA splicing on transcriptome remodeling in the heart

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