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hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2

Malignant characteristics of cancers, represented by rapid cell proliferation and high metastatic potential, are a major cause of high cancer-related mortality. As a multifunctional RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) is closely associated with cancer progression...

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Autores principales: Lee, Woo Joo, Shin, Chang Hoon, Ji, Haein, Jeong, Seong Dong, Park, Mi-So, Won, Hong-Hee, Pandey, Poonam R., Tsitsipatis, Dimitrios, Gorospe, Myriam, Kim, Hyeon Ho
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969774/
https://www.ncbi.nlm.nih.gov/pubmed/33731671
http://dx.doi.org/10.1038/s41419-021-03575-1
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author Lee, Woo Joo
Shin, Chang Hoon
Ji, Haein
Jeong, Seong Dong
Park, Mi-So
Won, Hong-Hee
Pandey, Poonam R.
Tsitsipatis, Dimitrios
Gorospe, Myriam
Kim, Hyeon Ho
author_facet Lee, Woo Joo
Shin, Chang Hoon
Ji, Haein
Jeong, Seong Dong
Park, Mi-So
Won, Hong-Hee
Pandey, Poonam R.
Tsitsipatis, Dimitrios
Gorospe, Myriam
Kim, Hyeon Ho
author_sort Lee, Woo Joo
collection PubMed
description Malignant characteristics of cancers, represented by rapid cell proliferation and high metastatic potential, are a major cause of high cancer-related mortality. As a multifunctional RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) is closely associated with cancer progression in various types of cancers. In this study, we sought to identify hnRNPK-regulated long intergenic non-coding RNAs (lincRNAs) that play a critical role in the regulation of cancer malignancy. We found that hnRNPK controlled malignant phenotypes including invasiveness, proliferation, and clonogenicity. RNA sequencing and functional studies revealed that LINC00263, a novel target of hnRNPK, is involved in the oncogenic functions of hnRNPK. Knockdown of LINC00263 mitigated the malignant capabilities. Conversely, increased malignant phenotypes were observed in LINC00263-overexpressing cells. Since LINC00263 was mainly localized in the cytosol and highly enriched in Argonaute 2-immunoprecipitation (Ago2-IP), we hypothesized that LINC00263 acts as a competitive endogenous RNA (ceRNA), and thus sought to identify LINC00263-associated microRNAs. Using small RNA sequencing followed by antisense oligonucleotide pull-down, miR-147a was selected for further study. We found that miR-147a negatively regulates LINC00263 via direct interaction, thus suppressing malignant capabilities. Moreover, knockdown of hnRNPK and LINC00263 upregulated miR-147a, indicating that LINC00263 serves as a ceRNA for miR-147a. By analyzing RNA sequencing data and miRNA target prediction, calpain 2 (CAPN2) was identified as a putative target of miR-147a. Ago2-IP and luciferase reporter assay revealed that miR-147a suppressed CAPN2 expression by directly binding to the 3′UTR of CAPN2 mRNA. In addition, we found that the weakened malignant capabilities following knockdown of hnRNPK or LINC00263 were restored by miR-147a inhibition or CAPN2 overexpression. Furthermore, our findings were validated in various other types of cancer cells including lung cancer, colorectal cancer, neuroblastoma, and melanoma. Collectively, we demonstrate that hnRNPK-regulated LINC00263 plays an important role in cancer malignancy by acting as a miR-147a decoy and thus upregulating CAPN2.
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spelling pubmed-79697742021-04-12 hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2 Lee, Woo Joo Shin, Chang Hoon Ji, Haein Jeong, Seong Dong Park, Mi-So Won, Hong-Hee Pandey, Poonam R. Tsitsipatis, Dimitrios Gorospe, Myriam Kim, Hyeon Ho Cell Death Dis Article Malignant characteristics of cancers, represented by rapid cell proliferation and high metastatic potential, are a major cause of high cancer-related mortality. As a multifunctional RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) is closely associated with cancer progression in various types of cancers. In this study, we sought to identify hnRNPK-regulated long intergenic non-coding RNAs (lincRNAs) that play a critical role in the regulation of cancer malignancy. We found that hnRNPK controlled malignant phenotypes including invasiveness, proliferation, and clonogenicity. RNA sequencing and functional studies revealed that LINC00263, a novel target of hnRNPK, is involved in the oncogenic functions of hnRNPK. Knockdown of LINC00263 mitigated the malignant capabilities. Conversely, increased malignant phenotypes were observed in LINC00263-overexpressing cells. Since LINC00263 was mainly localized in the cytosol and highly enriched in Argonaute 2-immunoprecipitation (Ago2-IP), we hypothesized that LINC00263 acts as a competitive endogenous RNA (ceRNA), and thus sought to identify LINC00263-associated microRNAs. Using small RNA sequencing followed by antisense oligonucleotide pull-down, miR-147a was selected for further study. We found that miR-147a negatively regulates LINC00263 via direct interaction, thus suppressing malignant capabilities. Moreover, knockdown of hnRNPK and LINC00263 upregulated miR-147a, indicating that LINC00263 serves as a ceRNA for miR-147a. By analyzing RNA sequencing data and miRNA target prediction, calpain 2 (CAPN2) was identified as a putative target of miR-147a. Ago2-IP and luciferase reporter assay revealed that miR-147a suppressed CAPN2 expression by directly binding to the 3′UTR of CAPN2 mRNA. In addition, we found that the weakened malignant capabilities following knockdown of hnRNPK or LINC00263 were restored by miR-147a inhibition or CAPN2 overexpression. Furthermore, our findings were validated in various other types of cancer cells including lung cancer, colorectal cancer, neuroblastoma, and melanoma. Collectively, we demonstrate that hnRNPK-regulated LINC00263 plays an important role in cancer malignancy by acting as a miR-147a decoy and thus upregulating CAPN2. Nature Publishing Group UK 2021-03-17 /pmc/articles/PMC7969774/ /pubmed/33731671 http://dx.doi.org/10.1038/s41419-021-03575-1 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Lee, Woo Joo
Shin, Chang Hoon
Ji, Haein
Jeong, Seong Dong
Park, Mi-So
Won, Hong-Hee
Pandey, Poonam R.
Tsitsipatis, Dimitrios
Gorospe, Myriam
Kim, Hyeon Ho
hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2
title hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2
title_full hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2
title_fullStr hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2
title_full_unstemmed hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2
title_short hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2
title_sort hnrnpk-regulated linc00263 promotes malignant phenotypes through mir-147a/capn2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969774/
https://www.ncbi.nlm.nih.gov/pubmed/33731671
http://dx.doi.org/10.1038/s41419-021-03575-1
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