CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer
Abstract Background Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear. Methods RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic duct...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Shi Chen [verfasserIn] Can Yang [verfasserIn] Zu-Wei Wang [verfasserIn] Jian-Fei Hu [verfasserIn] Jing-Jing Pan [verfasserIn] Cheng-Yu Liao [verfasserIn] Jia-Qiang Zhang [verfasserIn] Jiang-Zhi Chen [verfasserIn] Yi Huang [verfasserIn] Long Huang [verfasserIn] Qian Zhan [verfasserIn] Yi-Feng Tian [verfasserIn] Bai-Yong Shen [verfasserIn] Yao-Dong Wang [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2021 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
In: Journal of Hematology & Oncology - BMC, 2008, 14(2021), 1, Seite 24 |
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| Übergeordnetes Werk: |
volume:14 ; year:2021 ; number:1 ; pages:24 |
| Links: |
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| DOI / URN: |
10.1186/s13045-021-01072-8 |
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| Katalog-ID: |
DOAJ07368970X |
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| 245 | 1 | 0 | |a CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer |
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| 520 | |a Abstract Background Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear. Methods RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5250-Ser (SRSF5250-Ser) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14exon10 (METTL14exon10) and Cyclin L2exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14exon 10 and Cyclin L2exon6.3 skipping were surveyed. Results CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5250-Ser, which inhibited METTL14exon10 skipping while promoted Cyclin L2exon6.3 skipping. In addition, aberrant METTL14exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2exon6.3 promoted proliferation of PDAC cells. Conclusions The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. This study suggests the potential prognostic value and therapeutic targeting of this pathway in PDAC patients. | ||
| 650 | 4 | |a Pancreatic cancer | |
| 650 | 4 | |a Alternative splicing | |
| 650 | 4 | |a CLK1 | |
| 650 | 4 | |a SRSF5 | |
| 650 | 4 | |a M6A Modification | |
| 650 | 4 | |a METTL14 | |
| 653 | 0 | |a Diseases of the blood and blood-forming organs | |
| 653 | 0 | |a Neoplasms. Tumors. Oncology. Including cancer and carcinogens | |
| 700 | 0 | |a Can Yang |e verfasserin |4 aut | |
| 700 | 0 | |a Zu-Wei Wang |e verfasserin |4 aut | |
| 700 | 0 | |a Jian-Fei Hu |e verfasserin |4 aut | |
| 700 | 0 | |a Jing-Jing Pan |e verfasserin |4 aut | |
| 700 | 0 | |a Cheng-Yu Liao |e verfasserin |4 aut | |
| 700 | 0 | |a Jia-Qiang Zhang |e verfasserin |4 aut | |
| 700 | 0 | |a Jiang-Zhi Chen |e verfasserin |4 aut | |
| 700 | 0 | |a Yi Huang |e verfasserin |4 aut | |
| 700 | 0 | |a Long Huang |e verfasserin |4 aut | |
| 700 | 0 | |a Qian Zhan |e verfasserin |4 aut | |
| 700 | 0 | |a Yi-Feng Tian |e verfasserin |4 aut | |
| 700 | 0 | |a Bai-Yong Shen |e verfasserin |4 aut | |
| 700 | 0 | |a Yao-Dong Wang |e verfasserin |4 aut | |
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10.1186/s13045-021-01072-8 doi (DE-627)DOAJ07368970X (DE-599)DOAJ01d7197874484cb79bff06aee64ec8cf DE-627 ger DE-627 rakwb eng RC633-647.5 RC254-282 Shi Chen verfasserin aut CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear. Methods RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5250-Ser (SRSF5250-Ser) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14exon10 (METTL14exon10) and Cyclin L2exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14exon 10 and Cyclin L2exon6.3 skipping were surveyed. Results CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5250-Ser, which inhibited METTL14exon10 skipping while promoted Cyclin L2exon6.3 skipping. In addition, aberrant METTL14exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2exon6.3 promoted proliferation of PDAC cells. Conclusions The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. This study suggests the potential prognostic value and therapeutic targeting of this pathway in PDAC patients. Pancreatic cancer Alternative splicing CLK1 SRSF5 M6A Modification METTL14 Diseases of the blood and blood-forming organs Neoplasms. Tumors. Oncology. Including cancer and carcinogens Can Yang verfasserin aut Zu-Wei Wang verfasserin aut Jian-Fei Hu verfasserin aut Jing-Jing Pan verfasserin aut Cheng-Yu Liao verfasserin aut Jia-Qiang Zhang verfasserin aut Jiang-Zhi Chen verfasserin aut Yi Huang verfasserin aut Long Huang verfasserin aut Qian Zhan verfasserin aut Yi-Feng Tian verfasserin aut Bai-Yong Shen verfasserin aut Yao-Dong Wang verfasserin aut In Journal of Hematology & Oncology BMC, 2008 14(2021), 1, Seite 24 (DE-627)568914813 (DE-600)2429631-4 17568722 nnns volume:14 year:2021 number:1 pages:24 https://doi.org/10.1186/s13045-021-01072-8 kostenfrei https://doaj.org/article/01d7197874484cb79bff06aee64ec8cf kostenfrei https://doi.org/10.1186/s13045-021-01072-8 kostenfrei https://doaj.org/toc/1756-8722 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2021 1 24 |
| spelling |
10.1186/s13045-021-01072-8 doi (DE-627)DOAJ07368970X (DE-599)DOAJ01d7197874484cb79bff06aee64ec8cf DE-627 ger DE-627 rakwb eng RC633-647.5 RC254-282 Shi Chen verfasserin aut CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear. Methods RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5250-Ser (SRSF5250-Ser) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14exon10 (METTL14exon10) and Cyclin L2exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14exon 10 and Cyclin L2exon6.3 skipping were surveyed. Results CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5250-Ser, which inhibited METTL14exon10 skipping while promoted Cyclin L2exon6.3 skipping. In addition, aberrant METTL14exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2exon6.3 promoted proliferation of PDAC cells. Conclusions The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. This study suggests the potential prognostic value and therapeutic targeting of this pathway in PDAC patients. Pancreatic cancer Alternative splicing CLK1 SRSF5 M6A Modification METTL14 Diseases of the blood and blood-forming organs Neoplasms. Tumors. Oncology. Including cancer and carcinogens Can Yang verfasserin aut Zu-Wei Wang verfasserin aut Jian-Fei Hu verfasserin aut Jing-Jing Pan verfasserin aut Cheng-Yu Liao verfasserin aut Jia-Qiang Zhang verfasserin aut Jiang-Zhi Chen verfasserin aut Yi Huang verfasserin aut Long Huang verfasserin aut Qian Zhan verfasserin aut Yi-Feng Tian verfasserin aut Bai-Yong Shen verfasserin aut Yao-Dong Wang verfasserin aut In Journal of Hematology & Oncology BMC, 2008 14(2021), 1, Seite 24 (DE-627)568914813 (DE-600)2429631-4 17568722 nnns volume:14 year:2021 number:1 pages:24 https://doi.org/10.1186/s13045-021-01072-8 kostenfrei https://doaj.org/article/01d7197874484cb79bff06aee64ec8cf kostenfrei https://doi.org/10.1186/s13045-021-01072-8 kostenfrei https://doaj.org/toc/1756-8722 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2021 1 24 |
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10.1186/s13045-021-01072-8 doi (DE-627)DOAJ07368970X (DE-599)DOAJ01d7197874484cb79bff06aee64ec8cf DE-627 ger DE-627 rakwb eng RC633-647.5 RC254-282 Shi Chen verfasserin aut CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear. Methods RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5250-Ser (SRSF5250-Ser) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14exon10 (METTL14exon10) and Cyclin L2exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14exon 10 and Cyclin L2exon6.3 skipping were surveyed. Results CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5250-Ser, which inhibited METTL14exon10 skipping while promoted Cyclin L2exon6.3 skipping. In addition, aberrant METTL14exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2exon6.3 promoted proliferation of PDAC cells. Conclusions The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. This study suggests the potential prognostic value and therapeutic targeting of this pathway in PDAC patients. Pancreatic cancer Alternative splicing CLK1 SRSF5 M6A Modification METTL14 Diseases of the blood and blood-forming organs Neoplasms. Tumors. Oncology. Including cancer and carcinogens Can Yang verfasserin aut Zu-Wei Wang verfasserin aut Jian-Fei Hu verfasserin aut Jing-Jing Pan verfasserin aut Cheng-Yu Liao verfasserin aut Jia-Qiang Zhang verfasserin aut Jiang-Zhi Chen verfasserin aut Yi Huang verfasserin aut Long Huang verfasserin aut Qian Zhan verfasserin aut Yi-Feng Tian verfasserin aut Bai-Yong Shen verfasserin aut Yao-Dong Wang verfasserin aut In Journal of Hematology & Oncology BMC, 2008 14(2021), 1, Seite 24 (DE-627)568914813 (DE-600)2429631-4 17568722 nnns volume:14 year:2021 number:1 pages:24 https://doi.org/10.1186/s13045-021-01072-8 kostenfrei https://doaj.org/article/01d7197874484cb79bff06aee64ec8cf kostenfrei https://doi.org/10.1186/s13045-021-01072-8 kostenfrei https://doaj.org/toc/1756-8722 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2021 1 24 |
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10.1186/s13045-021-01072-8 doi (DE-627)DOAJ07368970X (DE-599)DOAJ01d7197874484cb79bff06aee64ec8cf DE-627 ger DE-627 rakwb eng RC633-647.5 RC254-282 Shi Chen verfasserin aut CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear. Methods RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5250-Ser (SRSF5250-Ser) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14exon10 (METTL14exon10) and Cyclin L2exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14exon 10 and Cyclin L2exon6.3 skipping were surveyed. Results CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5250-Ser, which inhibited METTL14exon10 skipping while promoted Cyclin L2exon6.3 skipping. In addition, aberrant METTL14exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2exon6.3 promoted proliferation of PDAC cells. Conclusions The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. This study suggests the potential prognostic value and therapeutic targeting of this pathway in PDAC patients. Pancreatic cancer Alternative splicing CLK1 SRSF5 M6A Modification METTL14 Diseases of the blood and blood-forming organs Neoplasms. Tumors. Oncology. Including cancer and carcinogens Can Yang verfasserin aut Zu-Wei Wang verfasserin aut Jian-Fei Hu verfasserin aut Jing-Jing Pan verfasserin aut Cheng-Yu Liao verfasserin aut Jia-Qiang Zhang verfasserin aut Jiang-Zhi Chen verfasserin aut Yi Huang verfasserin aut Long Huang verfasserin aut Qian Zhan verfasserin aut Yi-Feng Tian verfasserin aut Bai-Yong Shen verfasserin aut Yao-Dong Wang verfasserin aut In Journal of Hematology & Oncology BMC, 2008 14(2021), 1, Seite 24 (DE-627)568914813 (DE-600)2429631-4 17568722 nnns volume:14 year:2021 number:1 pages:24 https://doi.org/10.1186/s13045-021-01072-8 kostenfrei https://doaj.org/article/01d7197874484cb79bff06aee64ec8cf kostenfrei https://doi.org/10.1186/s13045-021-01072-8 kostenfrei https://doaj.org/toc/1756-8722 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2021 1 24 |
| allfieldsSound |
10.1186/s13045-021-01072-8 doi (DE-627)DOAJ07368970X (DE-599)DOAJ01d7197874484cb79bff06aee64ec8cf DE-627 ger DE-627 rakwb eng RC633-647.5 RC254-282 Shi Chen verfasserin aut CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear. Methods RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5250-Ser (SRSF5250-Ser) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14exon10 (METTL14exon10) and Cyclin L2exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14exon 10 and Cyclin L2exon6.3 skipping were surveyed. Results CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5250-Ser, which inhibited METTL14exon10 skipping while promoted Cyclin L2exon6.3 skipping. In addition, aberrant METTL14exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2exon6.3 promoted proliferation of PDAC cells. Conclusions The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. This study suggests the potential prognostic value and therapeutic targeting of this pathway in PDAC patients. Pancreatic cancer Alternative splicing CLK1 SRSF5 M6A Modification METTL14 Diseases of the blood and blood-forming organs Neoplasms. Tumors. Oncology. Including cancer and carcinogens Can Yang verfasserin aut Zu-Wei Wang verfasserin aut Jian-Fei Hu verfasserin aut Jing-Jing Pan verfasserin aut Cheng-Yu Liao verfasserin aut Jia-Qiang Zhang verfasserin aut Jiang-Zhi Chen verfasserin aut Yi Huang verfasserin aut Long Huang verfasserin aut Qian Zhan verfasserin aut Yi-Feng Tian verfasserin aut Bai-Yong Shen verfasserin aut Yao-Dong Wang verfasserin aut In Journal of Hematology & Oncology BMC, 2008 14(2021), 1, Seite 24 (DE-627)568914813 (DE-600)2429631-4 17568722 nnns volume:14 year:2021 number:1 pages:24 https://doi.org/10.1186/s13045-021-01072-8 kostenfrei https://doaj.org/article/01d7197874484cb79bff06aee64ec8cf kostenfrei https://doi.org/10.1186/s13045-021-01072-8 kostenfrei https://doaj.org/toc/1756-8722 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2021 1 24 |
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Shi Chen @@aut@@ Can Yang @@aut@@ Zu-Wei Wang @@aut@@ Jian-Fei Hu @@aut@@ Jing-Jing Pan @@aut@@ Cheng-Yu Liao @@aut@@ Jia-Qiang Zhang @@aut@@ Jiang-Zhi Chen @@aut@@ Yi Huang @@aut@@ Long Huang @@aut@@ Qian Zhan @@aut@@ Yi-Feng Tian @@aut@@ Bai-Yong Shen @@aut@@ Yao-Dong Wang @@aut@@ |
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Methods RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5250-Ser (SRSF5250-Ser) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14exon10 (METTL14exon10) and Cyclin L2exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14exon 10 and Cyclin L2exon6.3 skipping were surveyed. Results CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5250-Ser, which inhibited METTL14exon10 skipping while promoted Cyclin L2exon6.3 skipping. In addition, aberrant METTL14exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2exon6.3 promoted proliferation of PDAC cells. Conclusions The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. 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Shi Chen |
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Shi Chen misc RC633-647.5 misc RC254-282 misc Pancreatic cancer misc Alternative splicing misc CLK1 misc SRSF5 misc M6A Modification misc METTL14 misc Diseases of the blood and blood-forming organs misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer |
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RC633-647.5 RC254-282 CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer Pancreatic cancer Alternative splicing CLK1 SRSF5 M6A Modification METTL14 |
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misc RC633-647.5 misc RC254-282 misc Pancreatic cancer misc Alternative splicing misc CLK1 misc SRSF5 misc M6A Modification misc METTL14 misc Diseases of the blood and blood-forming organs misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
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misc RC633-647.5 misc RC254-282 misc Pancreatic cancer misc Alternative splicing misc CLK1 misc SRSF5 misc M6A Modification misc METTL14 misc Diseases of the blood and blood-forming organs misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
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misc RC633-647.5 misc RC254-282 misc Pancreatic cancer misc Alternative splicing misc CLK1 misc SRSF5 misc M6A Modification misc METTL14 misc Diseases of the blood and blood-forming organs misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
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CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer |
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CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer |
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Shi Chen Can Yang Zu-Wei Wang Jian-Fei Hu Jing-Jing Pan Cheng-Yu Liao Jia-Qiang Zhang Jiang-Zhi Chen Yi Huang Long Huang Qian Zhan Yi-Feng Tian Bai-Yong Shen Yao-Dong Wang |
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clk1/srsf5 pathway induces aberrant exon skipping of mettl14 and cyclin l2 and promotes growth and metastasis of pancreatic cancer |
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RC633-647.5 |
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CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer |
| abstract |
Abstract Background Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear. Methods RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5250-Ser (SRSF5250-Ser) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14exon10 (METTL14exon10) and Cyclin L2exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14exon 10 and Cyclin L2exon6.3 skipping were surveyed. Results CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5250-Ser, which inhibited METTL14exon10 skipping while promoted Cyclin L2exon6.3 skipping. In addition, aberrant METTL14exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2exon6.3 promoted proliferation of PDAC cells. Conclusions The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. This study suggests the potential prognostic value and therapeutic targeting of this pathway in PDAC patients. |
| abstractGer |
Abstract Background Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear. Methods RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5250-Ser (SRSF5250-Ser) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14exon10 (METTL14exon10) and Cyclin L2exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14exon 10 and Cyclin L2exon6.3 skipping were surveyed. Results CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5250-Ser, which inhibited METTL14exon10 skipping while promoted Cyclin L2exon6.3 skipping. In addition, aberrant METTL14exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2exon6.3 promoted proliferation of PDAC cells. Conclusions The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. This study suggests the potential prognostic value and therapeutic targeting of this pathway in PDAC patients. |
| abstract_unstemmed |
Abstract Background Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear. Methods RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5250-Ser (SRSF5250-Ser) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14exon10 (METTL14exon10) and Cyclin L2exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14exon 10 and Cyclin L2exon6.3 skipping were surveyed. Results CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5250-Ser, which inhibited METTL14exon10 skipping while promoted Cyclin L2exon6.3 skipping. In addition, aberrant METTL14exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2exon6.3 promoted proliferation of PDAC cells. Conclusions The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. This study suggests the potential prognostic value and therapeutic targeting of this pathway in PDAC patients. |
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CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer |
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