CircMYLK promotes the growth, migration, invasion, and survival of bladder cancer cells by upregulating CCND3 level via competitively binding to miR‐34a

Abstract

Bladder cancer is one of the most common types of urothelial carcinoma with a rising incidence rate worldwide. Circular RNAs (circRNAs) are involved in the development of numerous cancers, including bladder cancer. We aimed to uncover the role and associated mechanism of circMYLK in bladder cancer. The expression levels of cir-cMYLK, miRNA-34a (miR-34a) and Cyclin D3 (CCND3) mRNA were investigated using real-time quantitative polymerase chain reaction. The protein level of CCND3 was investigated using western blot. In functional assays, flow cytometry assays were utilized for cell cycle analysis and cell apoptosis analysis. Transwell assays were used for cell migration and invasion analysis. Caspase-3 activity was examined to monitor cell apoptosis. The putative relationship between miR-34a and circMYLK or CCND3 was validated by dual-luciferase reporter assay and RNA immunoprecipitation assay.CircMYLK was highly expressed in bladder cancer tissues and cells. CircMYLK downregulation inhibited bladder cancer cell migration and invasion, and promoted cancer cell apoptosis and cell cycle arrest. MiR-34a, a target of circMYLK, was downregulated in bladder cancer tissues and cells. MiR-34a inhibition reversed the effects of circMYLK downregulation and then recovered bladder cell malignant behaviors.Further analysis showed that CCND3 was a downstream target of miR-34a, and CCND3 was upregulated in bladder cancer tissues and cells. MiR-34a overexpression blocked bladder cancer cell migration and invasion, and induced cell apoptosis and cycle arrest, while these effects were abolished by CCND3 overexpression. Cir-cMYLK contributed to the malignant development of bladder cancer cells partly through the miR-34a/CCND3 regulatory network, showing the significance of cir-cMYLK in bladder cancer pathogenesis.

Circular RNA MYLK as a prognostic biomarker in patients with cancers: A systematic review and meta‐analysis

“…Moreover, one review article and one investigation with only bioinformatic analysis were excluded after full‐text reviews (Figure 1 ). Ultimately, 12 studies were included in the qualitative synthesis of this review 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 21 , 22 (Table 1 ); however, three studies did not provide data regarding prognostic or clinicopathological features 12 , 21 , 22 ; therefore, nine articles were included in the meta‐analysis. Seven of these studies investigated the prognostic significance of circMYLK, and nine studies ascertained the clinicopathological importance of circMYLK in patients with malignancies.…”

“…All studies were from China and published between 2017 and 2021. Using the quantitative real‐time polymerase chain reaction (qRT‐PCR), the studies revealed upregulation of circMYLK in different malignant tissue samples, including bladder cancer, 7 , 8 HCC, 10 , 11 laryngeal cancer, 12 , 13 NSCLC, 9 renal cancer, 14 ovarian cancer, 15 prostate cancer, 22 cervical cancer, 21 and colorectal cancer. 16 According to these studies, circMYLK acts as a tumor promoter circRNA leading to migration, invasion, proliferation, and metastasis of neoplastic cells and inhibiting their apoptosis through interaction with several miRNAs and corresponding downstream signaling pathways.…”

“… 6 Based on the CircBase database annotation, circMYLK is spliced from the MYLK gene on chr3:123471177–123 512 691 and has a length of 376 nt. 7 Current investigations have found the oncogenic role of circMYLK, which is overexpressed in several cancer types, including bladder cancer, 7 , 8 non‐small‐cell lung cancer (NSCLC), 9 and hepatocellular carcinoma (HCC). 10 , 11 This circular transcript participates in cancer‐related critical pathways, such as VEGFA/VEGFR2, MEK/ERK, and NF‐κB pathways.…”

“… 7 , 12 Furthermore, several studies have suggested that circMYLK expression is associated with the various malignancies' prognosis and clinicopathological characteristics. 7 , 8 , 9 , 10 , 11 , 13 , 14 , 15 , 16 Despite these promising results, no prior studies have comprehensively reviewed the relationship between circMYLK expression and clinical outcomes of cancer patients. Herein, we carried out a systematic review and meta‐analysis to determine the role of circMYLK in cancer progression and provide a precise predictive value of circMYLK in the prognosis and clinicopathological features of patients with various cancers.…”

CircMCTP2 (has-circ-0000658) facilitates the proliferation and metastasis of bladder carcinoma through modulating the miR-498/murine double minute-2 axis

“…CircCEP128 deficiency represses the progression of BC through modulating themicroRNA-515-5p/SDC1 Axis [ 17 ]. CircMYLK increases the expression of CCND3 to facilitate the proliferation and metastasis of BC cells through sponging miR-34a [ 18 ]. CircNT5E speeds up the progression of BC by sponging miR-502-5p [ 19 ].…”