<p>Circular RNA Hsa_circ_0004018 Inhibits Wnt/β-Catenin Signaling Pathway by Targeting microRNA-626/DKK3 in Hepatocellular Carcinoma</p>

Abstract

Background and Aim: Dysexpression of circular RNAs has been identified in multiple types of cancer. Hsa_circ_0004018 was reported to be significantly downregulated in hepatocellular carcinoma (HCC) and to display HCC-stage-specific expression features. However, the role of hsa_circ_0004018 in HCC progression remains unclear. Methods: The expression of hsa_circ_0004018 or microRNA-626 (miR-626) was detected in tumor tissues and paired non-tumor tissues from HCC patients, as well as in one normal human liver cell line and 5 HCC cell lines by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, dye exclusion assay, clonogenic assay, scratch migration assay and transwell assay were used to measure cell proliferation and migration capacity, respectively. Luciferase report assay and RNA pull down assay were performed to explore the regulatory effect of certain molecules on the expression of target genes. Results: We found that the expression of hsa_circ_0004018 was lower in tumor tissues than in their paired non-tumor tissues from 28 out of 41 HCC patients. The difference in the expression between tumor tissues and non-tumor tissues was statistically significant (p<0.001). Further analysis revealed that such lower expression in tumor tissues was much more common in bigger tumor size group (≥5cm) compared with the smaller tumor size group (<5cm) (85% vs 42%, p=0.0007). Similarly, hsa_circ_0004018 was downregulated in HCC cell lines. Additionally, a negative correlation between hsa_circ_0004018 and miR-626 expression was noticed in HCC tissues. Moreover, we observed that hsa_circ_0004018 interacted with miR-626/DKK3 and contributed to HCC cell proliferation and migration through inhibiting Wnt/β-catenin signaling pathway in vitro. Furthermore, hsa_circ_0004018 blocked xenograft tumor growth in vivo through inhibiting Wnt/β-catenin signaling pathway by targeting miR-626/DKK3. Conclusion: We revealed that hsa_circ_0004018/miR-626/DKK3 regulatory axis may be a possible novel therapeutic target for HCC.

Bioinformatics Approach on Action and Mechanism of Bromelain in Hepatocellular Carcinoma

“…The research predicted that DKK3 is the potential target for gene miR-626. The inactivation of DKK3 will reduce the Wnt/β-catenin signaling and suppressed the spread of tumor in HCC conditions [10]. A similar effect is observed with the gene GSTZ1-1 [11].…”

Wnt/β‐catenin signaling pathway participates in the effect of miR‐626 on oral squamous cell carcinoma by targeting RASSF4

“…Similarly, Zhang M et al also found that RASSF4 overexpression inhibited the proliferation, invasion, and EMT of osteosarcoma cells through the Wnt/β‐catenin pathway 50 . Zhu P et al reported that the interaction of hsa_circ_0004018 and miR‐626/DKK3 with HCC proliferation and migration and xenograft tumor growth involves the Wnt/β‐catenin signaling pathway 11 . Additionally, aberrations in Wnt/β‐catenin are common during human carcinogenesis, which suggests that Wnt/β‐catenin is a major target for the treatment of cancers, including OSCC 51 .…”

Hsa_circ_0001073 targets miR‐626/LIFR axis to inhibit lung cancer progression

“…For instance, Zhu et al proposed that miR-626 promoted proliferation and migration of hepatocellular carcinoma cells. 15 Dong et al suggested that miR-626 was up-regulated and exerted an oncogenic role by targeting EYA4 in bladder cancer cells. 25 Similarly, we found the carcinogenic function of miR-626 in lung cancer.…”

“…14 miR-626 is up-regulated in hepatocellular carcinoma patients and promotes hepatocellular carcinoma cell proliferation and migration. 15 Leukemia inhibitory factor receptor (LIFR), a metastasis suppressor, represses cancer malignance in various cancers, including hepatocellular carcinoma, clear cell renal cell carcinoma and gastric cancer. [16][17][18] Moreover, LIFR can inhibit lung cancer cell invasion and metastasis, and it is mediated via circRNA Cysteine-Rich Transmembrane BMP Regulator 1 (circCRIM1)/miR-182/miR-93 axis.…”

“…High‐miR‐626 expression is associated with poor prognosis in oral squamous cell carcinoma, and may serve as a promising prognosis predictor 14 . miR‐626 is up‐regulated in hepatocellular carcinoma patients and promotes hepatocellular carcinoma cell proliferation and migration 15 . Leukemia inhibitory factor receptor (LIFR), a metastasis suppressor, represses cancer malignance in various cancers, including hepatocellular carcinoma, clear cell renal cell carcinoma and gastric cancer 16‐18 .…”