Abstract
Lung squamous carcinoma (LUSC) is a highly metastatic disease with a poor prognosis. Using an integrated screening approach, we found that miR-671-5p reduces LUSC metastasis by inhibiting a circular RNA (circRNA), CDR1as. Although the putative function of circRNA is through miRNA sponging, we found that miR-671-5pmore potently silenced an axis of CDR1as and its antisense transcript, cerebellar degeneration related protein 1 (CDR1). Silencing of CDR1as or CDR1 significantly inhibited LUSC metastases and CDR1 was sufficient to promote migration and metastases. CDR1, which directly interacted with adaptor protein 1 (AP1) complex subunits and coatomer protein I (COPI) proteins, no longer promoted migration upon blockade of Golgi trafficking. Therapeutic inhibition of the CDR1as/CDR1 axis with miR-671-5p mimics reduced metastasis in vivo. This report demonstrates a novel role for CDR1 in promoting metastasis and Golgi trafficking. These findings reveal an miRNA/ circRNA axis that regulates LUSC metastases through a previously unstudied protein, CDR1. Significance: This study shows that circRNA, CDR1as, promotes lung squamous migration, metastasis, and Golgi trafficking through its complimentary transcript, CDR1. Significance: This study shows that circRNA, CDR1as, promotes lung squamous migration, metastasis, and Golgi trafficking through its complimentary transcript, CDR1.
| Original language | English |
|---|---|
| Pages (from-to) | 4972-4985 |
| Number of pages | 14 |
| Journal | Cancer research |
| Volume | 80 |
| Issue number | 22 |
| DOIs | |
| State | Published - Nov 15 2020 |
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A circle RNA regulatory axis promotes lung squamous metastasis via CDR1-mediated regulation of golgi trafficking. / Harrison, Emily B.; Porrello, Alessandro; Bowman, Brittany M.; Belanger, Adam R.; Yacovone, Gabriella; Azam, Salma H.; Windham, Ian A.; Ghosh, Subrata K.; Wang, Menglin; McKenzie, Nicholas; Waugh, Trent A.; Van Swearingen, Amanda E.D.; Cohen, Stephanie M.; Allen, Devon G.; Goodwin, Tyler J.; Mascenik, Teresa; Bear, James E.; Cohen, Sarah; Randell, Scott H.; Massion, Pierre P.; Major, Michael B.; Huang, Leaf; Pecot, Chad V.
In: Cancer research, Vol. 80, No. 22, 15.11.2020, p. 4972-4985.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - A circle RNA regulatory axis promotes lung squamous metastasis via CDR1-mediated regulation of golgi trafficking
AU - Harrison, Emily B.
AU - Porrello, Alessandro
AU - Bowman, Brittany M.
AU - Belanger, Adam R.
AU - Yacovone, Gabriella
AU - Azam, Salma H.
AU - Windham, Ian A.
AU - Ghosh, Subrata K.
AU - Wang, Menglin
AU - McKenzie, Nicholas
AU - Waugh, Trent A.
AU - Van Swearingen, Amanda E.D.
AU - Cohen, Stephanie M.
AU - Allen, Devon G.
AU - Goodwin, Tyler J.
AU - Mascenik, Teresa
AU - Bear, James E.
AU - Cohen, Sarah
AU - Randell, Scott H.
AU - Massion, Pierre P.
AU - Major, Michael B.
AU - Huang, Leaf
AU - Pecot, Chad V.
N1 - Funding Information: The authors acknowledge members of the Pecot laboratory for helpful discussions and feedback. The authors would like to especially thank Drs. Yongjuan Xia and Nana Feinberg from the UNC Translational Pathology Laboratory for their help with ISH, IHC, and processing of the tissue microarrays and the UNC Animal Histopathology Core. Confocal microscopy was performed with equipment and assistance from the UNC Microscopy Services Laboratory, Department of Pathology and Laboratory Medicine. We also thank Dr. Antonio Amelio for providing the Fluorescent-Nanoluciferase plasmids and Drs. Gianpietro Dotti and Hongwei Du for GFP-luciferase labeling of cell lines. The authors acknowledge the following financial support: The UNC Translational Pathology Laboratory was supported, in part, by grants from the NCI (5P30CA016080-42), NIH (U54-CA156733), NIEHS (3P30 EOS010126-17), UCRF, and NCBT (2015-IDG-1007). C.V. Pecot was supported, in part, by the NIH grant no. R01CA215075, a Mentored Research Scholar Grants in Applied and Clinical Research (MRSG-14-222-01-RMC) from the American Cancer Society, the Jimmy V Foundation Scholar award, the UCRF Innovator Award, the Stuart Scott V Foundation/Lung Cancer Initiative Award for Clinical Research, the University Cancer Research Fund, the Lung Cancer Research Foundation, the Free to Breathe Metastasis Research Award, and the Susan G. Komen Career Catalyst Award. A.R. Belanger was supported by a grant from the National Heart, Lung and Blood Institute of the NIH under award number HL007106-38, an ASCO Young Investigator Award, and by the Lung Cancer Initiative of North Carolina. S.H. Azam and I.A. Windham were supported, in part, by a grant from the National Institute of General Medical Sciences under award 5T32 GM007092 and GM119999, respectively. E.B. Harrison was supported by a grant from the NCI of the NIH under award number T32CA196589 and by the Lung Cancer Initiative of North Carolina. S.M. Cohen and I.A. Windham were supported, in part, by an NIH R35 grant award number GM133460. S.H. Randell was supported, in part, by NIH 5P30DK065988. The UNC Microscopy Services Laboratory and Lineberger Comprehensive Cancer Center Animal Histopathology and Animal Studies Cores were all supported, in part, by an NCI Center Core Support grant (CA016086) to the UNC Lineberger Comprehensive Cancer Center. The UNC Flow Cytometry Core Facility was also supported, in part, by the North Carolina Biotech Center Institutional Support grant 2012-IDG-1006. Funding Information: The authors acknowledge members of the Pecot laboratory for helpful discussions and feedback. The authors would like to especially thank Drs. Yongjuan Xia and Nana Feinberg from the UNC Translational Pathology Laboratory for their help with ISH, IHC, and processing of the tissue microarrays and the UNC Animal Histopathology Core. Confocal microscopy was performed with equipment and assistance from the UNC Microscopy Services Laboratory, Department of Pathology and Laboratory Medicine. We also thank Dr. Antonio Amelio for providing the Fluorescent-Nanoluciferase plasmids and Drs. Gianpietro Dotti and Hongwei Du for GFP-luciferase labeling of cell lines. The authors acknowledge the following financial support: The UNC Translational Pathology Laboratory was supported, in part, by grants from the NCI (5P30CA016080-42), NIH (U54- CA156733), NIEHS (3P30 EOS010126-17), UCRF, and NCBT (2015-IDG-1007). C.V. Pecot was supported, in part, by the NIH grant no. R01CA215075, a Mentored Research Scholar Grants in Applied and Clinical Research (MRSG- 14-222-01-RMC) from the American Cancer Society, the Jimmy V Foundation Scholar award, the UCRF Innovator Award, the Stuart Scott V Foundation/Lung Cancer Initiative Award for Clinical Research, the University Cancer Research Fund, the Lung Cancer Research Foundation, the Free to Breathe Metastasis Research Award, and the Susan G. Komen Career Catalyst Award. A.R. Belanger was supported by a grant from the National Heart, Lung and Blood Institute of the NIH under award number HL007106-38, an ASCO Young Investigator Award, and by the Lung Cancer Initiative of North Carolina. S.H. Azam and I.A. Windham were supported, in part, by a grant from the National Institute of General Medical Sciences under award 5T32 GM007092 and GM119999, respectively. E.B. Harrison was supported by a grant from the NCI of the NIH under award number T32CA196589 and by the Lung Cancer Initiative of North Carolina. S.M. Cohen and I.A. Windham were supported, in part, by an NIH R35 grant award number GM133460. S.H. Randell was supported, in part, by NIH 5P30DK065988. The UNC Microscopy Services Laboratory and Lineberger Comprehensive Cancer Center Animal Histopathology and Animal Studies Cores were all supported, in part, by an NCI Center Core Support grant (CA016086) to the UNC Lineberger Comprehensive Cancer Center. The UNC Flow Cytometry Core Facility was also supported, in part, by the North Carolina Biotech Center Institutional Support grant 2012-IDG-1006. Funding Information: E.B. Harrison reports grants from Lung Cancer Initiative of North Carolina and NCI during the conduct of the study. A.E.D. Van Swearingen reports grants from NIH (R01CA215075) during the conduct of the study. T.J. Goodwin reports grants from NIH during the conduct of the study. S. Cohen reports grants from NIH during the conduct of the study, and NIH and Alzheimer's Association outside the submitted work. C.V. Pecot reports other compensation from EnFuego Therapeutics (founder and equity in a biotechnology company investigating RNA interference approaches to treat cancer) outside the submitted work. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: © 2020 American Association for Cancer Research.
PY - 2020/11/15
Y1 - 2020/11/15
N2 - Lung squamous carcinoma (LUSC) is a highly metastatic disease with a poor prognosis. Using an integrated screening approach, we found that miR-671-5p reduces LUSC metastasis by inhibiting a circular RNA (circRNA), CDR1as. Although the putative function of circRNA is through miRNA sponging, we found that miR-671-5pmore potently silenced an axis of CDR1as and its antisense transcript, cerebellar degeneration related protein 1 (CDR1). Silencing of CDR1as or CDR1 significantly inhibited LUSC metastases and CDR1 was sufficient to promote migration and metastases. CDR1, which directly interacted with adaptor protein 1 (AP1) complex subunits and coatomer protein I (COPI) proteins, no longer promoted migration upon blockade of Golgi trafficking. Therapeutic inhibition of the CDR1as/CDR1 axis with miR-671-5p mimics reduced metastasis in vivo. This report demonstrates a novel role for CDR1 in promoting metastasis and Golgi trafficking. These findings reveal an miRNA/ circRNA axis that regulates LUSC metastases through a previously unstudied protein, CDR1. Significance: This study shows that circRNA, CDR1as, promotes lung squamous migration, metastasis, and Golgi trafficking through its complimentary transcript, CDR1. Significance: This study shows that circRNA, CDR1as, promotes lung squamous migration, metastasis, and Golgi trafficking through its complimentary transcript, CDR1.
AB - Lung squamous carcinoma (LUSC) is a highly metastatic disease with a poor prognosis. Using an integrated screening approach, we found that miR-671-5p reduces LUSC metastasis by inhibiting a circular RNA (circRNA), CDR1as. Although the putative function of circRNA is through miRNA sponging, we found that miR-671-5pmore potently silenced an axis of CDR1as and its antisense transcript, cerebellar degeneration related protein 1 (CDR1). Silencing of CDR1as or CDR1 significantly inhibited LUSC metastases and CDR1 was sufficient to promote migration and metastases. CDR1, which directly interacted with adaptor protein 1 (AP1) complex subunits and coatomer protein I (COPI) proteins, no longer promoted migration upon blockade of Golgi trafficking. Therapeutic inhibition of the CDR1as/CDR1 axis with miR-671-5p mimics reduced metastasis in vivo. This report demonstrates a novel role for CDR1 in promoting metastasis and Golgi trafficking. These findings reveal an miRNA/ circRNA axis that regulates LUSC metastases through a previously unstudied protein, CDR1. Significance: This study shows that circRNA, CDR1as, promotes lung squamous migration, metastasis, and Golgi trafficking through its complimentary transcript, CDR1. Significance: This study shows that circRNA, CDR1as, promotes lung squamous migration, metastasis, and Golgi trafficking through its complimentary transcript, CDR1.
UR - http://www.scopus.com/inward/record.url?scp=85100302084&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-20-1162
DO - 10.1158/0008-5472.CAN-20-1162
M3 - Article
C2 - 32978168
AN - SCOPUS:85100302084
VL - 80
SP - 4972
EP - 4985
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 22
ER -