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Most of pituitary adenomas are biologically benign, but some grow local‐invasively and can invade important adjacent tissues, resulting in clinical symptoms such as hormone secretion disorders and visual field defects. MicroRNA‐221/222 (miR‐221/222) is tandemly encoded on the X chromosome in humans, mice and rats, and is highly conserved in vertebrates with the same seed sequence. To date, miR‐221/222 has been reported as either a tumor suppressor or a tumor promoter in different tumors, however, its role in pituitary tumors has not been elucidated. Our study aimed to investigate the effect and mechanism of miRNA‐221/222 in pituitary tumor cells. Results of real‐time quantitative PCR showed that the expression level of miRNA‐221/222 in plasma exosomes from patients with pituitary tumor was significantly higher than that from healthy people. Results of cell function experiments indicated that miRNA‐221/222 significantly promoted cell proliferation and migration, inhibited apoptosis and significantly inhibited the expression of Cleaved‐Caspase3 and E‐cadherin, while promoted the expression level of N‐cadherin. With transcriptome sequencing and comprehensive bioinformatics analysis, PHACTR4 was identified as the potential target gene of miRNA‐221/222 in regulating biological functions of pituitary adenoma cells. Dual luciferase reporter assay confirmed that PHACTR4 was the direct target gene of miRNA‐221/222 and overexpression of PHACTR4 gene reversed the regulatory effects of miRNA‐221/222. In vivo experiment of subcutaneous tumor formation in nude mice verified that miRNA‐221/222 promoted tumor growth by targeting PHACTR4. In conclusion, miRNA‐221/222 played the role of proto‐oncogene in the occurrence and development of pituitary tumors by targeting PHACTR4, which provided a new target for the diagnosis and molecular treatment of pituitary adenomas.

Breast malignancy remains one of the most common causes of cancer-associated mortalities among women. MicroRNA (miR)-221 and miR-222 are homologous miRs and have a substantial impact on cancer progression. In the present study, the regulatory mechanisms of miR-221/222 and its target annexin A3 (ANXA3) in breast cancer cells were investigated. Breast tissue samples were collected to evaluate the expression patterns of miR-221/222 levels in breast cancer cell lines and cancer tissues according to clinical characteristics. The levels of miR-221/222 were increased or decreased in cancer cell lines compared with normal breast cell lines according to cell line subtype. Subsequently, the changes in the progression and invasion of breast cancer cells were investigated using cell proliferation, invasion assay, gap closure and colony formation assays. Western blotting of cell cycle proteins and flow cytometry were performed to evaluate the possible pathway of miR-221/222 and ANXA3 axis. Chemosensitivity tests were performed to explore the suitability of the miR-221/222 and ANXA3 axis as a therapeutic target in breast cancer. The expression levels of miR-221/222 were associated with aggressive characteristics of breast cancer subtypes. Cell transfection assay demonstrated the regulation of breast cancer proliferation and invasiveness by miR-221/222. MiR-221/222 directly targeted the 3'-untranslated region of ANXA3 and suppressed the expression of ANXA3 at the mRNA and protein levels. In addition, miR-221/222 negatively regulated cell proliferation and the cell cycle pathway in breast cancer cells by targeting ANXA3. In combination with adriamycin, downregulation of ANXA3 may sensitize adriamycin-induced cell death to induction of persistent G2/M and G0/G1 arrest. Decreased expression of ANXA3 through increased expression of miR-221/222 reduced breast cancer progression and increased the effectiveness of the chemotherapy drug. The present results indicated the miR-221/222 and ANXA3 axis to be a possible novel therapeutic target for the treatment of breast cancer.

Atherosclerosis (AS) is the main aetiology of coronary heart disease, cerebral infarction and peripheral vascular disease in humans. Long‐noncoding RNA (LincRNA)‐p21 has been reported to participate in the development of AS. Therefore, this study was designed to investigate the mechanism of LincRNA‐p21 on suppressing the development of AS. We fed ApoE−/− mice with a high‐fat diet to induce an AS mouse model where the lesion area of AS and the extent of lipid deposition were measured. The binding of LincRNA‐p21 and miR‐221 or miR‐221 and SIRT1 was measured using a dual luciferase reporter gene assay and RIP. Following loss‐ and gain‐ function assays, CCK8, EdU, Transwell assay and scratch test were performed to determine the biological processes of human aortic endothelial cells (HAECs). miR‐221 was highly expressed while SIRT1 was poorly expressed in AS. LincRNA‐p21 acted as a sponge for miR‐221. miR‐221 targeted and negatively regulated the expression of SIRT1. LincRNA‐p21 promoted the deacetylation of Pcsk9 by SIRT1 by competitively binding to miR‐221, whereby promoting HAEC proliferation, migration and tube formation. In conclusion, LincRNA‐p21 acted as a molecular sponge for miR‐221 to promote deacetylation of the promoter region of Pcsk9 by SIRT1, therefore preventing the development of AS.

The expression levels of microRNA (miR)-221-3p and miR-222-3p in thyroid cancer have been found to be upregulated compared with those in normal tissues. The present study aimed to determine the effects and potential underlying mechanisms of miR-221-3p and miR-222-3p on the regulation of radioactive iodine (131I) uptake and radiosensitivity of thyroid cancer cells. The potential regulatory target genes of miR-221-3p and miR-222-3p were predicted by bioinformatics analysis, and reverse transcription-quantitative polymerase chain reaction was used to verify miR-221-3p, miR-222-3p and target gene expression levels in thyroid cancer tissues and cell lines. Overexpression of miR-221-3p or miR-222-3p in cell models was performed using lentivirus infection. Knockdown of miR-221-3p and miR-222-3p in cells was achieved using oligonucleotide inhibitor transfection. Western blotting was used to analyze the expression levels of target proteins. In addition, the effects of miR-221-3p and miR-222-3p on the radiosensitivity of thyroid cancer cells were verified using a colony formation assay. The results of the present study revealed that the expression levels of miR-221-3p and miR-222-3p were significantly upregulated, while the expression levels of suppressor of cytokine signaling 3 (SOCS3) were downregulated in thyroid cancer tissues. Furthermore, miR-221-3p and miR-222-3p overexpression downregulated the expression levels of SOCS3, E-cadherin and solute carrier family 5 member 5 (NIS), and upregulated the expression levels of phosphorylated STAT3 and vimentin. Following the overexpression of miR-221-3p or miR-222-3p in the FTC133 and TPC1 cell lines, their radiosensitivity was suppressed. In conclusion, the findings of the present study suggested that miR-221-3p and miR-222-3p may downregulate the expression levels of NIS and promote radioresistance. The potential mechanism was hypothesized to be associated with the miR-221-3p and miR-222-3p targeting of the SOCS3 gene, which may subsequently activate the STAT3 signaling pathway.

This study aims to investigate the anticancer effect of Oroxin B (OB) both in vitro and in vivo, and the molecular mechanism involved in microRNA-221 and the PI3K/Akt/PTEN pathway through modulation of apoptosis in Hepatocellular carcinoma (HCC). DEN-induced rats and HepG2 cells based on the microfluidic chip were employed, while the mRNA and protein expression of microRNA-221, PI3K, p-Akt and PTEN were evaluated by RT-PCR and Western blot analysis. Based on Microfluidic Chip and DEN-induced rat model, OB effectively exerts anti-liver cancer effect both in vitro and in vivo, and the expression of miR-221 in OB treated groups was significantly lower than that in the control group (** p < 0.01). The RT-PCR and Western blot results suggested the PI3K mRNA and protein in OB treated groups were both lower than those in control group and indicated the overexpression of PTEN. Therefore, OB effectively exerts anticancer effects by positively regulating the PTEN gene and then inactivating the PI3K/Akt signaling pathway through down-regulating the expression of the microRNA-221, thereby inducing apoptosis of liver cancer cells. This study offers a theoretical evidence for further development and clinical guidance of OB as an anti-tumor agent.

Intervertebral disc (IVD) degeneration (IDD) is closely associated with inflammation, oxidative stress and loss of the discogenic phenotype, which current therapies are unable to reverse. In the present study, the effects of acetone extract from Violina pumpkin (Cucurbita moschata) leaves on degenerated IVD cells were investigated. IVD cells were isolated from the degenerated disc tissue of patients undergoing spinal surgery and were exposed to acetone extract and three major thin layer chromatography subfractions. The results revealed that, in particular, the cells benefited from exposure to subfraction Fr7, which consisted almost entirely of p-Coumaric acid. Western blot and immunocytochemical analysis showed that Fr7 induced a significant increase in discogenic transcription factors (SOX9 and tricho-rhino-phalangeal syndrome type I protein, zinc finger protein), extracellular matrix components (aggrecan, collagen type II), cellular homeostasis and stress response regulators, such as FOXO3a, nuclear factor erythroid 2-related factor 2, superoxide dismutase 2 and sirtuin 1. Two important markers related to the presence and activity of stem cells, migratory capacity and OCT4 expression, were assessed by scratch assay and western blotting, respectively, and were significantly increased in Fr7-treated cells. Moreover, Fr7 counteracted H2O2-triggered cell damage, preventing increases in the pro-inflammatory and anti-chondrogenic microRNA (miR), miR-221. These findings strengthen the hypothesis that adequate stimuli can support resident cells to repopulate the degenerated IVD and restart the anabolic machinery. Taken together, these data contribute to the discovery of molecules potentially effective in slowing the progression of IDD, a disease for which there is currently no effective treatment. Moreover, the use of part of a plant, the pumpkin leaves, which is usually considered a waste product in the Western world, indicated that it contains substances with potential beneficial effects on human health.

Downregulation of miR-221-3p expression in prostate cancer (PCa) predicted overall and cancer-specific survival of high-risk PCa patients. Apart from PCa, miR-221-3p expression levels predicted a response to tyrosine kinase inhibitors (TKI) in clear cell renal cell carcinoma (ccRCC) patients. Since this role of miR-221-3p was explained with a specific targeting of VEGFR2, we examined whether miR-221-3p regulated VEGFR2 in PCa. First, we confirmed VEGFR2/KDR as a target gene of miR-221-3p in PCa cells by applying Luciferase reporter assays and Western blotting experiments. Although VEGFR2 was mainly downregulated in the PCa cohort of the TCGA (The Cancer Genome Atlas) database, VEGFR2 was upregulated in our high-risk PCa cohort (n = 142) and predicted clinical progression. In vitro miR-221-3p acted as an escape mechanism from TKI in PC3 cells, as displayed by proliferation and apoptosis assays. Moreover, we confirmed that Sunitinib induced an interferon-related gene signature in PC3 cells by analyzing external microarray data and by demonstrating a significant upregulation of miR-221-3p/miR-222-3p after Sunitinib exposure. Our findings bear a clinical perspective for high-risk PCa patients with low miR-221-3p levels since this could predict a favorable TKI response. Apart from this therapeutic niche, we identified a partially oncogenic function of miR-221-3p as an escape mechanism from VEGFR2 inhibition.

Reduced myocardial miR-221 expression is associated with severe cardiac fibrosis in heart failure patients. We aimed to demonstrate its mechanisms in cardioprotection and remodeling following myocardial infarction (MI). Using in vitro hypoxia and reoxygenation (H/R) of H9c2 and rat cardiac fibroblast (cFB) models, we found that miR-221 protects H9c2 through combined anti-apoptotic and anti-autophagic effects and cFB via anti-autophagic effects alone in H/R. It inhibits myofibroblast (myoFB) activation as indicated by lowering α-smooth muscle actin (α-SMA) expression, gel contraction, and collagen synthesis (Sircol assay). In vivo, following left coronary artery ligation (MI), rats were treated with miR-221 mimics (intravenous [i.v.], 1 mg/kg). With treatment, miR-221 increased by ∼15-fold in infarct and peri-infarct zones at day 2 post-MI. At days 7 and 30 post-MI, miR-221 reduced infarct size, fibrosis, and α-SMA+ cells in both infarct and remote myocardium. Left ventricle (LV) function was preserved as indicated by ejection fraction, infarct thickness, LV developed pressure, ±dP/dt, and end diastolic pressure. We demonstrated the anti-apoptotic and anti-autophagic effects were due to combined mechanisms of direct targeting on Bak1 and P53 and inhibition of phosphorylation at Ser46 and direct targeting on Ddit4, respectively. miR-221 enhances cardiomyocyte survival and protects cardiac function post-MI. It enhances cFB survival yet inhibits their activation, thus reducing adverse cardiac fibrosis. [Display omitted]

Glioma, the most common type of primary central nervous system cancers, was progressive with poor survival. MicroRNA, as a novel biomarker, was suspected to be novel biomarkers for glioma diagnosis and prognosis. The study aimed at investigating the diagnostic and predictive value of miR-221/222 family for glioma. In the first phase, we compared plasma miR-221/222 family levels between 50 glioma patients and 51 healthy controls by real-time qRT-PCR amplification. Meanwhile, a meta-analysis based on published studies and presents study was performed to explore the diagnostic performance of miR-221/222 family in human cancers. In the second phase, we correlated the miR-221/222 family expression level with prognosis of glioma using Kaplan-Meier survival curves. The plasma miR-221/222 family levels were found to be significantly upregulated in glioma patients ( P  = 0.001). The ROC curve analysis yielded an AUC values of 0.84 (95 % confidence interval (CI): 0.74–0.93) for miR-221 and 0.92 (95 % CI 0.87–0.94) for miR-222. In the meta-analysis, the summary receiver operating characteristic (sROC) was plotted with an AUC of 0.82 (95 % CI 0.78–0.85) for miR-221/222 family. It was also demonstrated that high positive plasma miR-221 and miR-222 were both correlated with poor survival rate (miR-221: HR = 2.13; 95 % CI, 1.05–4.31; miR-222: HR = 2.09; 95 % CI, 1.00–4.37). This study demonstrated that the detection of the miRNA-221/222 family should be considered as a new additional tool to better characterize glioma.

Prostate cancer (PCa) is globally the second most diagnosed malignancy in men, with >1.5 million new cases reported in 2020. Given the limitations of classical detection methods, the discovery of new predictive PCa biomarkers is critical. MicroRNAs (miRs), which are small, single-stranded, non-coding RNA molecules, have emerged as potential biomarkers for cancer diagnosis and prognosis. The present study aimed to evaluate the diagnostic value of miR-21 and miR-221 in PCa and their association with clinicopathological parameters. The expression of miR-21 and miR-221 was assessed using reverse transcription-quantitative PCR in 50 tumour and 50 control tissue samples. The results demonstrated that miR-21 and miR-221 were significantly upregulated in PCa tissues compared with that of the normal control tissues. Receiver operating characteristic curve analysis revealed that miR-21 had an area under the curve (AUC) of 0.90, with a sensitivity of 70% and a specificity of 96%. Similarly, miR-221 demonstrated an AUC of 0.89, with a sensitivity of 86% and a specificity of 78%. High expression of miR-21 and miR-221 was also demonstrated to be associated with higher Gleason scores and advanced tumour stages. The findings of the present study indicate the potential role of miR-21 and miR-221 as biomarkers in the diagnosis of PCa. However, further studies in non-invasive samples such as serum, blood and urine are needed to support the results of the present study.