Circular RNA (circRNA) is considered an important regulator of cancer. Circ_0001998 is a newly discovered circRNA and its role in lung adenocarcinoma (LUAD) remains obscure and requires further study. The expression levels of circ_0001998 and miR-145 in LUAD were predicted by bioinformatics analysis and then verified by qRT-PCR in the LUAD cell lines. CCK-8, clone formation, EdU assay, and flow cytometry were applied to determine the effects of silencing circ_0001998 on the viability, proliferation, and apoptosis of LUAD cells. The target relationship between circ_0001998 and miR-145 was predicted by bioinformatics analysis and verified by a luciferase activity experiment. The effect of circ_0001998/miR-145 axis on the viability, proliferation, and apoptosis of LUAD cells was verified by the rescue experiment. Circ_0001998 was upregulated in LUAD, and silencing circ_0001998 suppressed viability, proliferation, and invasion of LUAD cells. The target gene of circ_0001998, miR-145, was downregulated in LUAD, and the low expression of miR-145 indicated a poor prognosis. The effect of silencing circ_0001998 on the biological function of LUAD cells was reversed by the miR-145 inhibitor. Circ_0001998 regulates the proliferation, invasion, and apoptosis of LUAD via sponging miR-145.
Breast cancer (BC) is the most commonly diagnosed malignancy and the leading cause of cancer-related mortality among females. Over 90 % of the cases of death in BC patients are attributed to tumor cell metastasis. Therefore, it is urgently needed to investigate the molecular mechanisms of BC metastasis. The expression of miRNA in BC was evaluated by qRT-PCR and bioinformatics analysis. Clone formation, EdU assays, and subcutaneous xenograft model were used to test the growth of BC cells. Wound healing, transwell assays, and lung-metastasis model were used to explore the effect of miR-934 knockdown on cell metastasis. The miR-934 targets in BC were identified through bioinformatics analysis and luciferase reporter assays. The expression of protein was tested by western blot. The binding of mRNA and RNA-binding-protein was verified using RIP assays. miR-934 expression was significantly elevated in BC tissues, especially in those with lymph node metastasis and associated with poor patient prognosis. Experiments in vitro and in vivo showed that that upregulated miR-934 was not necessarily required for the growth of BC cells. However, miR-934 knockdown significantly inhibited the migration and invasion abilities of BC cells. Moreover, PTEN as identified as the direct target of miR-934 in BC, and miR-934 could promote BC cell metastasis by regulation of PTEN and epithelial–mesenchymal transition (EMT). Our results suggested that targeting miR-934 may be a practical treatment for BC cell metastasis.
Abnormal activation of Hedgehog (Hh) signaling pathway mediates the genesis and progression of various tumors [1] . Currently, three drugs targeting the Hh signaling component Smoothened (Smo) have been marketed for the clinical treatment of basal cell tumors or acute myeloid leukemia. However, drug resistance is a common problem in those drugs, so the study of Smo inhibitors that can overcome drug resistance has important guiding significance for clinical adjuvant drugs. MTT assay, clone formation assay and EdU assay were used to detect the proliferation inhibitory activity of the drugs on tumor cells. The effect of B13 on cell cycle and apoptosis were detected by flow cytometry. An acute toxicity test was used to detect the toxicity of B13 in vivo , and xenograft tumor model was used to detect the efficacy of B13 in vivo . The binding of B13 to Smo was studied by BODIPY-cyclopamine competitive binding assay and molecular docking. The effect of B13 on the expression and localization of downstream target gene Gli1/2 of Smo was investigated by Western Blot and immunofluorescence assay. Smo D473H mutant cell line was constructed to study the effect of B13 against drug resistance. (1) B13 had the strongest inhibitory activity against colorectal cancer cells. (2) B13 can effectively inhibit the clone formation and EdU positive rate of colon cancer cells. (3) B13 can block the cell cycle in the G2/M phase and cell apoptosis. (4) B13 has low toxicity in vivo , and its efficacy in vivo is better than that of the Vismodegib. (5) Molecular docking and BODIPY-cyclopamine experiments showed that B13 could bind to Smo protein. (6) B13 can inhibit the protein expression of Gli1, the downstream of Smo, and inhibit its entry into the nucleus. (7) B13 could inhibit the expression of Gli1 in the HEK293 cells with Smo D473H , and the molecular docking results showed that B13 could bind Smo D473H protein. B13 with the best anti-tumor activity was screened out by MTT assay. In vitro , pharmacodynamics experiments showed that B13 could effectively inhibit the proliferation and metastasis of colorectal cancer cells, induce cell cycle arrest, and induce cell apoptosis. In vivo pharmacodynamics experiments showed that B13 was superior to Vismodegib in antitumor activity and had low toxicity in vivo . Mechanism studies have shown that B13 can bind Smo protein, inhibit the expression of downstream Gli1 and its entry into the nucleus. Notably, B13 overcomes resistance caused by Smo D473H mutations.
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