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The transcribed ultraconserved element uc.51 promotes the proliferation and metastasis of breast cancer by stabilizing NONO

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Abstract

Long noncoding RNAs have recently emerged as significant contributors to cancers, including breast cancer (BC). One class of long noncoding RNAs called transcribed ultraconserved regions (T-UCRs) is highly conserved in many species and closely related to diverse physiological and pathological processes. However, the function of T-UCRs in BC remains largely unclear. In this study, we identified uc.51, a T-UCR that is overexpressed in both BC tissues and cell lines and is correlated with larger tumor size. Loss- and gain-of-function assays were performed in vitro and demonstrated that uc.51 promotes the proliferation, migration, and invasion of BC cells. Mechanistically, non-POU domain-containing octamer-binding protein (NONO) was found to physically interact with uc.51 by RNA pulldown followed by mass spectrometry. This interaction was further verified by RNA immunoprecipitation. Moreover, uc.51 positively regulated the expression of NONO, maintained its stability through the ubiquitin–proteasome system, and activated the phosphorylation of CREB. Rescue experiments demonstrated that NONO overexpression compensated for the attenuated influence on BC progression resulting from downregulation of uc.51, indicating that NONO functions downstream of uc.51. In vivo functional experiments also revealed a positive correlation between uc.51 expression and tumor size. Ki-67 and NONO levels in the lv-uc.51-shRNA group were decreased compared with those in the lv-con-shRNA group, according to the immunohistochemical staining results, and a decreased incidence of distant metastasis was observed in the lv-uc.51-shRNA group in the xenograft model. Collectively, our results reveal a substantial role for the uc.51-NONO axis in BC progression and indicate that the uc.51-NONO axis has potential to be a therapeutic target for BC.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

lncRNAs:

Long noncoding RNAs

BC:

Breast cancer

T-UCRs:

Transcribed ultraconserved regions

NONO:

Non-POU domain-containing octamer-binding protein

RIP:

RNA immunoprecipitation

ATCC:

American type culture collection

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

siRNAs:

Small interfering RNAs

shRNA:

Short hairpin RNA

qRT-PCR:

Quantitative real-time polymerase chain reaction

cDNA:

Complementary DNA

FISH:

Fluorescence in situ hybridization

CCK-8:

Cell Counting Kit-8

PBS:

Phosphate buffered saline

TBST:

Tris-buffered saline plus Tween

SDS:

Sodium dodecyl sulfate

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

PVDF:

Polyvinylidene fluoride

PBS:

Phosphate buffered solution

HRP:

Horseradish peroxidase

Co-IP:

Co-immuoprecipitation

IHC:

Immunohistochemistry

H&E:

Hematoxylin and eosin

RBP:

RNA-binding protein

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Acknowledgements

This research was supported in part by Jiangsu Province Six Talents Summit Project (WSW-001), Youth Talent Project (FRC201308), National Natural Science Foundation of China (81302305), and Natural Science Foundation of Jiangsu Province (BK20131027). We gratefully acknowledge the editorial assistance received from Changyan Ma, PhD.

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  1. Xiaoqing Shi, Xiaofeng Huang, and Rui Chen have contributed equally to this work.

Authors and Affiliations

  1. Department of Breast Disease, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210000, China

    Xiaoqing Shi, Xiaofeng Huang, Rui Chen, Yan Li, Yinggang Xu, Weiwei Zhang, Qiannan Zhu, Xiaoming Zha & Jue Wang

  2. Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210000, China

    Xiaoming Zha & Jue Wang

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Contributions

XS and XH contributed to the design and methodology of the study. XS and RC drafted the manuscript. YL, WZ, and YX participated in the acquisition and analysis of data. QZ was responsible for formal analysis. XZ and JW revised the study critically for important intellectual content and conducted quality control on it. All authors have read and approved the final manuscript.

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Correspondence to Xiaoming Zha or Jue Wang.

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All procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and those of the Helsinki Declaration. This work was approved by the ethics and research committee of the First Affiliated Hospital of Nanjing Medical University (2021-SRFA-175), and informed consent was obtained from all participants. Animal care and all the experimental protocols were approved by the Committee on the Ethics of Animal Experiments of Nanjing Medical University (IACUC-2002006–2).

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Shi, X., Huang, X., Chen, R. et al. The transcribed ultraconserved element uc.51 promotes the proliferation and metastasis of breast cancer by stabilizing NONO. Clin Exp Metastasis 38, 551–571 (2021). https://doi.org/10.1007/s10585-021-10128-5

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