Circular RNA hsa_circ_0005397 promotes hepatocellular carcinoma progression by regulating the miR‐326/PDK2 axis

Abstract

Introduction: Circular RNAs (circRNAs) are associated with the initiation and progression of cancer. However, the biological functions and underlying mechanism of hsa_circ_0005397 in hepatocellular carcinoma (HCC) have not been fully elucidated.Methods: Hemotoxylin and eosin staining was used to assess histological changes.The expression levels of hsa_circ_0005397, miR-326 and pyruvate dehydrogenase kinase 2 (PDK2) were measured by a quantitative real-time polymerase chain reaction. Cell proliferation was evaluated by cell counting kit-8 and colony formation assays. Cell cycle distribution and apoptosis were detected by flow cytometry analysis. Caspase-3 activity was determined by a caspase-3 activity kit. Wound healing and transwell assays were used to evaluate cell migration and invasion. A western blot assay was performed to measure the expression of cyclin D1, p21, matrix metalloproteinase (MMP)2, MMP9, PDK2 and PCNA. The interaction between miR-326 and hsa_circ_0005397 or PDK2 was confirmed by dual-luciferase reporter, RNA immunoprecipitation and RNA pull-down assays. Xenograft tumor models were established to confirm the role of hsa_circ_0005397 in vivo.Results: Hsa_circ_0005397 and PDK2 were up-regulated, whereas miR-326 was down-regulated in HCC tissues and cells. Hsa_circ_0005397 knockdown inhibited cell proliferation and metastasis, and promoted apoptosis. miR-326 was a direct target of hsa_circ_0005397, and inhibition of miR-326 reversed the inhibitory effect of hsa_circ_0005397 silencing on HCC progression. Moreover, PDK2 was a direct target of miR-326 and PDK2 overexpression abated the anti-cancer roles of miR-326 in HCC. Additionally, hsa_circ_0005397 regulated PDK2 expression by sponging miR-326. Furthermore, hsa_circ_0005397 down-regulation suppressed tumor growth by up-regulating miR-326 and down-regulating PDK2.Conclusions: Hsa_circ_0005397 facilitates HCC progression by regulating the miR-326/PDK2 axis, providing a promising circRNA-targeted therapy for HCC.

Hsa_circ_0005397 promotes hepatocellular carcinoma progression through EIF4A3

“…For instance, hsa_circ_0005397 was upregulated and promoted cell proliferation and invasion in pancreatic cancer [ 33 ]. More importantly, hsa_circ_0005397 was overexpressed in HCC tissues, which could promote hepatocellular carcinoma progression by regulating the miR-326/PDK2 axis [ 21 ]. In this study, we also verified that hsa_circ_0005397 were markedly overexpressed in both HCC tissues and cell lines.…”

“…Moreover, hsa_circ_0068631 recruits EIF4A3, which increases expression of c-Myc in breast cancer, showing an important role in cancer metastasis [ 20 ]. As reported, hsa_circ_0005397 is a kind of circRNA originating from RHOT1 that promotes HCC by regulating the miR-326/PDK2 axis [ 21 ]. Hsa_circ_0005397 might also be involved in other pathogeneses with various binding sites.…”

CircUCK2 promotes hepatocellular carcinoma development by upregulating UCK2 in a mir-149-5p-dependent manner

“…For example, circ_101555 contributed to HCC cell growth and transferability by segregating miR-145-5p from CDCA3 [ 9 ]. Circ_0005397 expedited the advancement of HCC by modulating miR-326/PDK2 axis [ 10 ]. CircUCK2 (hsa_circ_0006758), derived from uridine–cytidine kinase 2 (UCK2) mRNA, is a circRNA with largely unknown function.…”

Circ_0073228 serves as a competitive endogenous ribonucleic acid to facilitate proliferation and inhibit apoptosis of hepatocellular carcinoma cells by the miR‐139‐5p/deoxyribonuclease II axis

“…To date, one of the most famous theories is the miRNA “sponge”, which illustrates that lncRNAs or circRNAs target miRNAs, and then indirectly modulate the expression of mRNAs, the targeted genes of miRNAs 13,14 . Accumulating studies have reported that circRNAs can sponge or bind with miRNAs to regulate the targeted gene expression levels in HCC 15–17 . For example, circNEIL3 promotes cell proliferative, migrative, and invasive behaviors and stimulates cell cycle arrest and apoptosis in HCC via the miR‐3150b‐3p/LAMC1 axis 18 .…”

“…13,14 Accumulating studies have reported that circRNAs can sponge or bind with miRNAs to regulate the targeted gene expression levels in HCC. [15][16][17] For example, circNEIL3 promotes cell proliferative, migrative, and invasive behaviors and stimulates cell cycle arrest and apoptosis in HCC via the miR-3150b-3p/LAMC1 axis. 18 CircARPP21 sponges miR-543 to attenuate proliferation and mobility of HCC cells via LIFR.…”