Circular RNA expression pattern and competing endogenous RNA network involved in rotator cuff tendinopathy_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

GE Zilu , ZHOU Binghua , ZHENG Xiaolong , YANG Mingyu , LÜ Jingtong , DENG Honghao ,  TANG Kanglai ,  CHEN Wan

Department of Orthopeadics/Sports Medicine Center, the First Affiliated Hospital of the Army Medical University, Chongqing, 400038, P.R.China;

Corresponding author：

TANG Kanglai, Email: tangkanglai@hotmail.com; CHEN Wan, Email: chenwanfred@foxmail.com

Keywords：

Rotator cuff tendinopathy; circular RNA; profile; RNA-sequence; competing endogenous RNA

DOI：

10.7507/1002-1892.201911094

Video：

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Objective To detect the differentially expressed circular RNA (circRNA) in rotator cuff tendinopathy and analyze the potential molecular mechanism of these parental genes.Methods Ten supraspinatus tendons donated from patients who underwent tendon repair surgery between June 2018 and June 2019 were used for RNA-sequence. All rotator cuff tendinopathy and normal tendon samples were confirmed by MRI, histological staining, and observation by arthroscopy. All pathological tendons were matched with tendon samples for patients’ age, gender, body mass index, and Bonar score. The bioinformatic analysis was performed based on the differentially expressed circRNA and their parental genes, including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and competing endogenous RNA (ceRNA) network construction.Results There were 94 differentially expressed circRNAs, including 31 up-regulated and 63 down-regulated, detected between the rotator cuff tendinopathy and normal tendon samples with |log2 fold change (FC)| >2, P<0.05. GO analysis showed that the genes were mostly enriched in response to cyclic adenosine monophosphate (cAMP). KEGG pathway analysis showed that the most genes were enriched in extracellular matrix-receptor interaction, protein digestion and absorption, cell cycle, and nuclear factor κB signaling pathway. ceRNA networks showed the interactions among circRNAs, mRNAs, and miRNAs. And circRNA.8951-has-miR-6089-DNMT3B was the most sum max energy.Conclusion This bioinformatic study reveals several potential therapeutic targets for rotator cuff tendinopathy, which paves the way to better treatment and prevention of this disorder.

Citation： GE Zilu, ZHOU Binghua, ZHENG Xiaolong, YANG Mingyu, LÜ Jingtong, DENG Honghao, TANG Kanglai, CHEN Wan. Circular RNA expression pattern and competing endogenous RNA network involved in rotator cuff tendinopathy. Chinese Journal of Reparative and Reconstructive Surgery, 2020, 34(5): 608-614. doi: 10.7507/1002-1892.201911094 Copy

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2.	Lewis J, Mccreesh K, Roy JS, et al. Rotator cuff tendinopathy: navigating the diagnosis-management conundrum. J Orthop Sports Phys Ther, 2015, 45(11): 923-937.
3.	Lewis JS. Rotator cuff tendinopathy. Br J Sports Med, 2009, 43(4): 236-241.
4.	Robertson CM, Chen CT, Shindle MK, et al. Failed healing of rotator cuff repair correlates with altered collagenase and gelatinase in supraspinatus and subscapularis tendons. Am J Sports Med, 2012, 40(9): 1993-2001.
5.	Kristensen LS, Andersen MS, Stagsted LVW, et al. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet, 2019, 20(11): 675-691.
6.	Liu CX, Li X, Nan F, et al. Structure and degradation of circular RNAs regulate PKR activation in innate immunity. Cell, 2019, 177(4): 865-880.e21.
7.	Guarnerio J, Zhang Y, Cheloni G, et al. Intragenic antagonistic roles of protein and circRNA in tumorigenesis. Cell Res, 2019, 29(8): 628-640.
8.	Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature, 2013, 495(7441): 333-338.
9.	Deng G, Mou T, He J, et al. Circular RNA circRHOBTB3 acts as a sponge for miR-654-3p inhibiting gastric cancer growth. J Exp Clin Cancer Res, 2020, 39(1): 1.
10.	Yang SJ, Wang DD, Zhou SY, et al. Identification of circRNA-miRNA networks for exploring an underlying prognosis strategy for breast cancer. Epigenomics, 2020, 12(2): 101-125.
11.	Lu YF, Liu Y, Fu WM, et al. Long noncoding RNA H19 accelerates tenogenic differentiation and promotes tendon healing through targeting miR-29b-3p and activating TGF-1 signaling. FASEB J, 2016, 31(3): 954-964.
12.	Maffulli N, Longo UG, Franceschi F, et al. Movin and bonar scores assess the same characteristics of tendon histology. Clin Orthop Relat Res, 2008, 466(7): 1605-1611.
13.	Lewis JS. Rotator cuff tendinopathy/subacromial impingement syndrome: is it time for a new method of assessment? Br J Sports Med, 2009, 43(4): 259-264.
14.	Beard DJ, Rees JL, Cook JA, et al. Arthroscopic subacromial decompression for subacromial shoulder pain (CSAW): a multicentre, pragmatic, parallel group, placebo-controlled, three-group, randomised surgical trial. Lancet, 2018, 391(10118): 329-338.
15.	Kim SH. Bioinformatics analysis in differences of RNA expression in the tendon according to anatomic outcomes in rotator cuff repair: response. Am J Sports Med, 2017, 45(13): NP30-NP31.
16.	Plachel F, Heuberer P, Gehwolf R, et al. MicroRNA profiling reveals distinct signatures in degenerative rotator cuff pathologies. J Orthop Res, 2020, 38(1): 202-211.
17.	Zhang Q, Ge H, Jiang Y, et al. Microarray profiling analysis of long non-coding RNAs expression in tendinopathy: identification for potential biomarkers and mechanisms. Int J Exp Pathol, 2015, 96(6): 387-394.
18.	Roesler WJ. What is a cAMP response unit? Mol Cell Endocrinol, 2000, 162(1-2): 1-7.
19.	Tucci MA, Barbieri RA, Freeland AE. Biochemical and histological analysis of the flexor tenosynovium in patients with carpal tunnel syndrome. Biomed Sci Instrum, 1997, 33: 246-251.
20.	Kasai T, Nakatani M, Ishiguro N, et al. Promethazine hydrochloride inhibits ectopic fat cell formation in skeletal muscle. Am J Pathol, 2017, 187(12): 2627-2634.
21.	Hayden MS, Ghosh S. NF-κB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev, 2012, 26(3): 203-234.
22.	Millar NL, Hueber AJ, Reilly JH, et al. Inflammation is present in early human tendinopathy. Am J Sports Med, 2010, 38(10): 2085-2091.
23.	Abraham AC, Shah SA, Golman M, et al. Targeting the NF-kappaB signaling pathway in chronic tendon disease. Sci Transl Med, 2019, 11(481). doi: 10.1126/scitranslmed.aav4319.
24.	Poulsen RC, Carr AJ, Hulley PA. Protection against glucocorticoid-induced damage in human tenocytes by modulation of ERK, Akt, and forkhead signaling. Endocrinology, 2011, 152(2): 503-514.
25.	Wei X, Li H, Yang J, et al. Circular RNA profiling reveals an abundant circLMO7 that regulates myoblasts differentiation and survival by sponging miR-378a-3p. Cell Death Dis, 2017, 8(10): e3153.
26.	Lu YF, Liu Y, Fu WM, et al. Long noncoding RNA H19 accelerates tenogenic differentiation and promotes tendon healing through targeting miR-29b-3p and activating TGF-β1 signaling. FASEB J, 2017, 31(3): 954-964.
27.	Cipollaro L, Sahemey R, Oliva F, et al. Immunohistochemical features of rotator cuff tendinopathy. Br Med Bull, 2019, 130(1): 105-123.
28.	Dakin SG, Newton J, Martinez FO, et al. Chronic inflammation is a feature of Achilles tendinopathy and rupture. Br J Sports Med, 2018, 52(6): 359-367.
29.	Zhou R, Wu Y, Wang W, et al. Circular RNAs (circRNAs) in cancer. Cancer Lett, 2018, 425: 134-142.
30.	Ho J, Chan H, Wong SH, et al. The involvement of regulatory non-coding RNAs in sepsis: a systematic review. Crit Care, 2016, 20(1): 383.

1. Ostör AJK, Richards CA, Prevost AT, et al. Diagnosis and relation to general health of shoulder disorders presenting to primary care. Rheumatology (Oxford), 2005, 44(6): 800-805.
2. Lewis J, Mccreesh K, Roy JS, et al. Rotator cuff tendinopathy: navigating the diagnosis-management conundrum. J Orthop Sports Phys Ther, 2015, 45(11): 923-937.
3. Lewis JS. Rotator cuff tendinopathy. Br J Sports Med, 2009, 43(4): 236-241.
4. Robertson CM, Chen CT, Shindle MK, et al. Failed healing of rotator cuff repair correlates with altered collagenase and gelatinase in supraspinatus and subscapularis tendons. Am J Sports Med, 2012, 40(9): 1993-2001.
5. Kristensen LS, Andersen MS, Stagsted LVW, et al. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet, 2019, 20(11): 675-691.
6. Liu CX, Li X, Nan F, et al. Structure and degradation of circular RNAs regulate PKR activation in innate immunity. Cell, 2019, 177(4): 865-880.e21.
7. Guarnerio J, Zhang Y, Cheloni G, et al. Intragenic antagonistic roles of protein and circRNA in tumorigenesis. Cell Res, 2019, 29(8): 628-640.
8. Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature, 2013, 495(7441): 333-338.
9. Deng G, Mou T, He J, et al. Circular RNA circRHOBTB3 acts as a sponge for miR-654-3p inhibiting gastric cancer growth. J Exp Clin Cancer Res, 2020, 39(1): 1.
10. Yang SJ, Wang DD, Zhou SY, et al. Identification of circRNA-miRNA networks for exploring an underlying prognosis strategy for breast cancer. Epigenomics, 2020, 12(2): 101-125.
11. Lu YF, Liu Y, Fu WM, et al. Long noncoding RNA H19 accelerates tenogenic differentiation and promotes tendon healing through targeting miR-29b-3p and activating TGF-1 signaling. FASEB J, 2016, 31(3): 954-964.
12. Maffulli N, Longo UG, Franceschi F, et al. Movin and bonar scores assess the same characteristics of tendon histology. Clin Orthop Relat Res, 2008, 466(7): 1605-1611.
13. Lewis JS. Rotator cuff tendinopathy/subacromial impingement syndrome: is it time for a new method of assessment? Br J Sports Med, 2009, 43(4): 259-264.
14. Beard DJ, Rees JL, Cook JA, et al. Arthroscopic subacromial decompression for subacromial shoulder pain (CSAW): a multicentre, pragmatic, parallel group, placebo-controlled, three-group, randomised surgical trial. Lancet, 2018, 391(10118): 329-338.
15. Kim SH. Bioinformatics analysis in differences of RNA expression in the tendon according to anatomic outcomes in rotator cuff repair: response. Am J Sports Med, 2017, 45(13): NP30-NP31.
16. Plachel F, Heuberer P, Gehwolf R, et al. MicroRNA profiling reveals distinct signatures in degenerative rotator cuff pathologies. J Orthop Res, 2020, 38(1): 202-211.
17. Zhang Q, Ge H, Jiang Y, et al. Microarray profiling analysis of long non-coding RNAs expression in tendinopathy: identification for potential biomarkers and mechanisms. Int J Exp Pathol, 2015, 96(6): 387-394.
18. Roesler WJ. What is a cAMP response unit? Mol Cell Endocrinol, 2000, 162(1-2): 1-7.
19. Tucci MA, Barbieri RA, Freeland AE. Biochemical and histological analysis of the flexor tenosynovium in patients with carpal tunnel syndrome. Biomed Sci Instrum, 1997, 33: 246-251.
20. Kasai T, Nakatani M, Ishiguro N, et al. Promethazine hydrochloride inhibits ectopic fat cell formation in skeletal muscle. Am J Pathol, 2017, 187(12): 2627-2634.
21. Hayden MS, Ghosh S. NF-κB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev, 2012, 26(3): 203-234.
22. Millar NL, Hueber AJ, Reilly JH, et al. Inflammation is present in early human tendinopathy. Am J Sports Med, 2010, 38(10): 2085-2091.
23. Abraham AC, Shah SA, Golman M, et al. Targeting the NF-kappaB signaling pathway in chronic tendon disease. Sci Transl Med, 2019, 11(481). doi: 10.1126/scitranslmed.aav4319.
24. Poulsen RC, Carr AJ, Hulley PA. Protection against glucocorticoid-induced damage in human tenocytes by modulation of ERK, Akt, and forkhead signaling. Endocrinology, 2011, 152(2): 503-514.
25. Wei X, Li H, Yang J, et al. Circular RNA profiling reveals an abundant circLMO7 that regulates myoblasts differentiation and survival by sponging miR-378a-3p. Cell Death Dis, 2017, 8(10): e3153.
26. Lu YF, Liu Y, Fu WM, et al. Long noncoding RNA H19 accelerates tenogenic differentiation and promotes tendon healing through targeting miR-29b-3p and activating TGF-β1 signaling. FASEB J, 2017, 31(3): 954-964.
27. Cipollaro L, Sahemey R, Oliva F, et al. Immunohistochemical features of rotator cuff tendinopathy. Br Med Bull, 2019, 130(1): 105-123.
28. Dakin SG, Newton J, Martinez FO, et al. Chronic inflammation is a feature of Achilles tendinopathy and rupture. Br J Sports Med, 2018, 52(6): 359-367.
29. Zhou R, Wu Y, Wang W, et al. Circular RNAs (circRNAs) in cancer. Cancer Lett, 2018, 425: 134-142.
30. Ho J, Chan H, Wong SH, et al. The involvement of regulatory non-coding RNAs in sepsis: a systematic review. Crit Care, 2016, 20(1): 383.

Chinese Journal of Reparative and Reconstructive Surgery

Circular RNA expression pattern and competing endogenous RNA network involved in rotator cuff tendinopathy

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