A novel intronic circular RNA, circGNG7, inhibits head and neck squamous cell carcinoma progression by blocking the phosphorylation of heat shock protein 27 at Ser78 and Ser82

Abstract

Background There is increasing evidence that circular RNAs (circRNAs) play a significant role in pathological processes including tumorigenesis. In contrast to exonic circRNAs, which are the most frequently reported circRNAs in cancer so far, the studies of intronic circRNAs have been greatly lagged behind. Here, we aimed to investigate the regulatory role of intronic circRNAs in head and neck squamous cell carcinoma (HNSCC). Methods We conducted whole‐transcriptome sequencing with four pairs of primary tumor tissues and adjacent normal tissues from HNSCC patients. Then, we characterized circGNG7 expression in HNSCC tissues and cell lines and explored its association with the prognosis of HNSCC patients. We also identified interactions between circGNG7 and functional proteins, which alter downstream signaling that regulate HNSCC progression. Results In this study, we identified a new intronic circRNA, circGNG7, and validated its functional roles in HNSCC progression. CircGNG7 was predominately localized to the cytoplasm, and its expression was downregulated in both HNSCC tissues andCAL27, CAL33, SCC4, SCC9, HN6, and HN30 cells. Low expression of circGNG7 was significantly correlated with poor prognosis in HNSCC patients. Consistent with this finding, overexpression of circGNG7 strongly inhibited tumor cell proliferation, colony formation, in vitro migration, and in vivo tumor growth. Mechanistically, the expression of circGNG7 in HNSCC cells was regulated by the transcription factor SMAD family member 4 (SMAD4). Importantly, we discovered that circGNG7 could bind to serine residues 78 and 82 of the functional heat shock protein 27 (HSP27), occupying its phosphorylation sites and hindering its phosphorylation, which reduced HSP27‐JNK/P38 mitogen‐activated protein kinase (MAPK) oncogenic signaling. Downregulation of circGNG7 expression in HNSCC increased HSP27‐JNK/P38 MAPK signaling and promoted tumor progression. Conclusions Our results revealed that a new intronic circRNA, circGNG7, functions as a strong tumor suppressor and that circGNG7/HSP27‐JNK/P38 MAPK signaling is a novel mechanism by which HNSCC progression can be controlled.

Diagnostic and prognostic value ofcircRNAsexpression in head and neck squamous cell carcinoma: A meta‐analysis

“…Finally, 55 articles that involved details regarding 56 unique circRNAs and 5,576 HNSCC cases (all cases were reliably diagnosed via histopathological analysis) were included in this meta‐analysis. To be specific, we included 31 diagnostic studies (from 23 articles 25–47 ), 38 prognostic studies (from 38 articles 25–30,48–79 ), and 27 clinical‐pathological feature‐related studies(from 26 articles 28,29,43,47,48,50,51,53,55,56,58,63–68,70–74,76–79 ).…”

Long non-coding RNA human leucocyte antigen complex group-18 HCG18 (HCG18) promoted cell proliferation and migration in head and neck squamous cell carcinoma through cyclin D1-WNT pathway

“…The Magna RIP™ RNA-Binding Protein Immunoprecipitation Kit (17–700, Millipore) was used to perform RIP experiments[ 14 ]. SCC4 cells were transfected with cyclin D1 overexpressed plasmid or control plasmid and lysed.…”

Editorial: “Non-Coding RNAs in Head and Neck Squamous Cell Carcinoma”

“…In addition, a few circRNAs can directly interact with proteins and enzymes as protein scaffolds. For instance, circRNA G protein subunit gamma 7 (circGNG7) inhibits HNSCC cell proliferation by binding to serine residues 78 and 82 of Heat shock protein 27 (HSP27) ( 70 ). CircRNA FAT atypical cadherin 1(circFAT1) prevents STAT3 dephosphorylation by binding to STAT3, resulting in HNSCC stemness and immune evasion ( 71 ).…”