Oncogenic circDHTKD1 promotes tumor growth and metastasis of oral squamous cell carcinoma in vitro and in vivo via upregulating miR-326-mediated GAB1

Abstract

Circular RNAs (circRNAs) have been extensively elucidated with regard to their significant implications in oral squamous cell carcinoma (OSCC). This study performed the functional investigation of circRNA dehydrogenase E1 and transketolase domain containing 1 (circDHTKD1) in OSCC. RNA expression levels of different molecules were measured via quantitative real-time polymerase chain reaction (qRT-PCR). Cellular behaviors were detected by 3-(4, 5-dimethylthiazol-2-y1)-2,5-diphenyl tetrazolium bromide (MTT) for cell viability, colony formation assay for clonal capacity, flow cytometry for cell apoptosis, wound healing assay for migration, and transwell assay for migration/invasion. Western blot was used for analyzing protein expression. RNA pull-down and dual-luciferase reporter assays were applied to assess the binding between targets. A xenograft tumor model was established in nude mice for in vivo experiments. Our expression analysis revealed that circDHTKD1 was upregulated in OSCC tissues and cells. circDHTKD1 knockdown was shown to impede OSCC cell growth and metastasis but motivate apoptosis. Additionally, circDHTKD1 served as a microRNA-326 (miR-326) sponge and the function of circDHTKD1 was achieved by sponging miR-326 in OSCC cells. Also, miR-326 inhibited OSCC development via targeting GRB2-associated-binding protein 1 (GAB1). circDHTKD1 could sponge miR-326 to alter GAB1 expression. Furthermore, circDHTKD1 contributed to OSCC progression in vivo via the miR-326/GAB1 axis. These data disclosed a specific circDHTKD1/miR-326/GAB1 signal axis in governing the malignant progression of OSCC, showing the considerable possibility of circDHTKD1 as a predictive and therapeutic target for clinical diagnosis and treatment of OSCC.

Prognostic significance of CircRNAs expression in oral squamous cell carcinoma

“…After reviewing the full‐text articles, 56 records were excluded whose data were insufficient and six were removed with no relevant outcomes reported (Table ). In total, 1813 OSCC patients from 26 studies were finally included in the meta‐analysis (Chen et al, 2020; Chen et al, 2020; Chen et al, 2021; Chen et al, 2018; Dou et al, 2020; Dou et al, 2019; Gao et al, 2020; Hao et al, 2020; Jiang et al, 2021; Li et al, 2021a; Liu et al, 2021; Luo et al, 2020; Ouyang et al, 2018; Peng et al, 2020; Qian et al, 2021; Qian et al, 2021; Wang et al, 2020; Wu et al, 2021; Xia et al, 2019; Yang et al, 2020; Yang et al, 2021; Yao et al, 2020; Zeng et al, 2021; Zhang et al, 2021; Zhao et al, 2020; Zhu et al, 2020). Among these articles, 19 had data related to prognostic analysis, and 22 articles reported information required for clinicopathological analysis.…”

“…Twenty‐two studies consisting of 1506 cases and involved with twenty‐two circRNAs (hsa_circ_0001874, hsa_circ_0001971, circ‐MMP9, circ_0001742, ciRS‐7, circ‐ABCB10, circRNA_002178, circUHRF1, circEPSTI1, circ_0000199, circ_BICD2 7, circ‐LRP6, circVAPA, circHIPK3, circBCL11B, circDHTKD1, circ_0000003, hsa_circ_0092125, circATRNL1, circ_0000140, circ‐ITCH, and Hsa_circ_0043265) were enrolled in the meta‐analysis of clinicopathological parameters (Chen et al, 2020; Chen et al, 2020; Chen et al, 2021; Chen et al, 2018; Dou et al, 2020; Gao et al, 2020; Hao et al, 2020; Jiang et al, 2021; Luo et al, 2020; Peng et al, 2020; Qian et al, 2021; Qian et al, 2021; Wang et al, 2020; Wu et al, 2021; Xia et al, 2019; Yang et al, 2020; Yao et al, 2020; Zeng et al, 2021; Zhang et al, 2021; Zhao et al, 2020; Zhu et al, 2020). The correlations between circRNAs expression and OSCC clinicopathological characteristics (including age, gender, tumor site, histological differentiation, lymph node metastasis, distant metastasis, TNM stage, and tumor stage) were presented in Table ( p < 0.05 suggests statistical significance) which indicated that all of the twenty‐two circRNAs were related to at least one clinicopathological parameters (e.g., TNM stage).…”

LncRNA DLEU1 facilitates the progression of oral squamous cell carcinoma by miR‐126‐5p/GAB1 axis

“…GAB1 is frequently aberrant in cancerous tissues and cells, and is related to OSCC progression. 16 It has been previously reported that repressed GAB1 can affect B-cell receptor signaling in chronic lymphocytic leukemia. 28 Upregulated GAB1 facilitates breast cancer metastasis via dissociation of the polarity-associated partitioning defective (PAR) complex.…”

“…Having revealed the vital function of miR‐126‐5p in the suppression of OSCC progression, the potential mechanisms were then explored. GAB1 is frequently aberrant in cancerous tissues and cells, and is related to OSCC progression 16 . It has been previously reported that repressed GAB1 can affect B‐cell receptor signaling in chronic lymphocytic leukemia 28 .…”

“…15 Oncogenic circDHTKD1 increases the proliferation and metastasis of OSCC by elevating GAB1 mediated by miR-326 in vitro and in vivo. 16 The StarBase database showed the probable binding relationship of miR-126-5p and GAB1 mRNA, whereas their interaction in OSCC is still ambiguous.…”