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Breast cancer (BRCA) is one of the major threats to women's health worldwide. This study focuses on the roles of sorbin and SH3 domain-containing protein 2 (SORBS2) protein and microRNA-138-5p in the progression of BRCA, analyzing their regulatory effects on cancer cell proliferation, cell cycle, and migration ability. Using bioinformatics tools and experimental methods, the study found that SORBS2 is commonly underexpressed in BRCA. Additionally, it demonstrated that microRNA-138-5p can significantly inhibit tumor growth by suppressing SORBS2 expression, providing new molecular targets for BRCA treatment., (© 2024 Wiley Periodicals LLC.)

Both circular RNA eukaryotic translation initiation factor 6 (circEIF6) and microRNA (miR)-138-5p participate in thyroid cancer (TC) progression. Nevertheless, the relationship between them remains under-explored. Hence, this research ascertained the mechanism of circEIF6 in TC via miR-138-5p. After TC tissues and cells were harvested, circEIF6, miR-138-5p, and lipase H (LIPH) levels were assessed. The binding relationships among circEIF6, miR-138-5p, and LIPH were analyzed. The impacts of circEIF6, miR-138-5p, and LIPH on the invasive and proliferative abilities of TPC-1 cells were examined by Transwell and EdU assays. Tumor xenograft in nude mice was established for in vivo validation of the impact of circEIF6. CircEIF6 expression was high in TC cells and tissues. Additionally, miR-138-5p was poor and LIPH level was high in TC tissues. Mechanistically, circEIF6 competitively bound to miR-138-5p to elevate LIPH via a competitive endogenous RNA mechanism. Silencing of circEIF6 reduced TPC-1 cell proliferative and invasive properties, which was annulled by further inhibiting miR-138-5p or overexpressing LIPH. Likewise, circEIF6 silencing repressed the growth of transplanted tumors, augmented miR-138-5p expression, and diminished LIPH expression in nude mice. Conclusively, circEIF6 silencing reduced LIPH level by competitive binding to miR-138-5p, thus subduing the proliferation and invasion of TPC-1 cells., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Long non‑coding RNAs (lncRNAs) and microRNAs (miRNAs) are essential for the progression of tumors, including cutaneous squamous cell carcinoma (CSCC). The present study aimed to examine the competing endogenous RNA (ceRNA) network in CSCC. Differentially expressed genes in CSCC were analyzed using the GSE66359 microarray data set, and the upstream miRNAs and lncRNAs were predicted using online database analysis (TargetScan 7.1, mirDIP 4.1, miRSearch V3.0, miRDB and RNA22 2.0) and were verified in clinical tissues. RNA pull‑down and dual luciferase reporter gene assays were used to verify the targeting relationships among lncRNA human histocompatibility leukocyte antigen complex P5 (HCP5), miR‑138‑5p and enhancer of zeste homolog 2 (EZH2). Cell lines with a high and low HCP5 expression were screened, and a pcDNA‑3.1‑HCP5 overexpression vector, small interfering RNA against HCP5, miR‑138‑5p mimics and miR‑138‑5p inhibitors were transfected into the CSCC cells. Cell viability, invasion, migration, apoptotic rate and autophagy were evaluated. The effects of HCP5 on autophagy and apoptosis of CSCC cells were verified in vivo using Ki67 and TUNEL staining. EZH2 was demonstrated to be upregulated in CSCC cells. miR‑138‑5p target sequences were identified in HCP5 and EZH2. HCP5 was revealed to function as a putative ceRNA of miR‑138‑5p to positively regulate EZH2, and EZH2 was shown to regulate autophagy and apoptosis of CSCC cells through the STAT3/VEGFR2 pathway. HCP5 overexpression decreased miR‑138‑5p levels, increased EZH2 levels and promoted cell malignant behaviors and autophagy but decreased the apoptosis rate. These trends were opposite when HCP5 was silenced. In conclusion, HCP5 may competitively bind to miR‑138‑5p to regulate EZH2 in CSCC cells, promoting autophagy and reducing apoptosis through the STAT3/VEGFR2 pathway. This study may provide a new perspective for understanding the molecular mechanism and treatment of CSCC.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Concern was raised about the reliability of the Western blot results in Figs. 2B and 5I+J, which appear to have the same eyebrow shaped phenotype as many other publications tabulated here (https://docs.google.com/spreadsheets/d/149EjFXVxpwkBXYJOnOHb6RhAqT4a2llhj9LM60MBffM/edit#gid=0). In addition, Fig. 4B appears to show a digital composition of xenografted tumors. The journal requested the corresponding author comment on these concerns and provide the raw data. However the authors were not able to satisfactorily fulfil this request and therefore the Editor-in-Chief decided to retract the article., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rationale: Differential activation of macrophages correlates closely with tumor progression, and the epigenetic factor lysine demethylase 6B (KDM6B, previously named JMJD3) mediates the regulation of macrophage polarization through an unknown mechanism. Methods: We developed a suspension coculture system comprising breast cancer cells and macrophages and used RT-qPCR and western blotting to measure KDM6B expression. Bioinformatics and luciferase reporter assays were used to identify candidate microRNAs of cancer cells responsible for the downregulation of KDM6B. To determine if exosomes mediated the transfer of miR-138-5p between cancer cells to macrophages, we treated macrophages with exosomes collected from the conditioned medium of cancer cells. The effects of exosomal miR-138-5p on macrophage polarization were measured using RT-qPCR, flow cytometry, and chromatin immunoprecipitation assays. We employed a mouse model of breast cancer, metastatic to the lung, to evaluate the effects on tumor metastasis of macrophages treated with miR-138-5p-enriched exosomes. To develop a diagnostic evaluation index, the levels of exosomal miR-138-5p in samples from patients with breast cancer were compared to those of controls. Results: Coculture of breast cancer cells led to downregulation of KDM6B expression in macrophages. Cancer cell-derived exosomal miR-138-5p inhibited M1 polarization and promoted M2 polarization through inhibition of KDM6B expression in macrophages. Macrophages treated with exosomal miR-138-5p promoted lung metastasis, and the level of circulating exosomal miR-138-5p positively correlated with the progression of breast cancer. Conclusion: Our data suggest that miR-138-5p was delivered from breast cancer cells to tumor-associated macrophages via exosomes to downregulate KDM6B expression, inhibit M1 polarization, and stimulate M2 polarization. Therefore, exosomal miR-138-5p represents a promising prognostic marker and target for the treatment of breast cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The present study aimed to investigate the regulatory effects of microRNA‑138‑5p (miR‑138‑5p) and sirtuin 1 (SIRT1) on the progression of heart failure (HF). The binding association between miR‑138‑5p and SIRT1 was assessed by the dual‑luciferase reporter assay. By conducting reverse transcription‑quantitative polymerase chain reaction and Western blotting, relative levels of SIRT1 and p53 regulated by miR‑138‑5p were detected. In vitro HF models were generated by hydrogen peroxide (H 2 O 2 ) induction in AC‑16 and human cardiomyocyte (HCM) cells, followed by detection of the regulatory effects of SIRT1 on cell apoptosis and p53 expression. MiR‑138‑5p was negatively correlated with the SIRT1 level in cardiomyocytes. By recognizing and specifically targeting SIRT1 3'‑untranslated region (3'‑UTR), miR‑138‑5p decreased the translational level of SIRT1 and inhibited its enzyme activity, thereby decreasing the deacetylation level of p53. Through downregulating SIRT1 and activating p53 signaling, miR‑138‑5p induced apoptosis in H 2 O 2 ‑induced AC‑16 and HCM cells. By contrast, knockdown of miR‑138‑5p in the in vitro HF models significantly protected the cardiomyocytes. SIRT1 contributed toward alleviate HF by inhibiting cardiomyocyte apoptosis via enhancing the deacetylation level of p53. MiR‑138‑5p decreases the enzyme activity of SIRT1 by specifically targeting its 3'‑UTR and activates p53 signaling, followed by triggering cardiomyocyte apoptosis during the process of HF. It is considered that miR‑138‑5p and SIRT1 may be potential diagnostic biomarkers and therapeutic targets for HF.

MicroRNAs (miRs) play an important role in the development and progression of spinal cord injury (SCI). The role of miR‑138‑5p in SCI was investigated in the present study. The anti‑inflammatory effects of miR‑138‑5p and underlying mechanisms were investigated in an SCI rat model and in vitro model. Reverse transcription‑quantitative PCR (RT‑qPCR) was used to examine the expression of miR‑138‑5p in the SCI in vivo and in vitro models, as well as patients with SCI; it was found that miR‑138‑5p was significantly upregulated in SCI. Bioinformatics and dual‑luciferase reporter assays were performed to predict and confirm the binding sites between miR‑138‑5p and the 3'untranslated region of sirtuin 1 (SIRT1). Then, the expression of SIRT1 was detected via RT‑qPCR and western blotting, indicating downregulation of SIRT1 in SCI. PC12 cells were transfected with miR‑138‑5p inhibitor, inhibitor control or miR‑138‑5p inhibitor + SIRT1 small interfering RNA for 48 h, and then subjected to lipopolysaccharide (100 ng/ml) treatment for 4 h. Then, MTT assay, flow cytometry and ELISA experiments were performed to analyze cell viability, apoptosis, and the levels of tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑6. Findings suggested that downregulation of miR‑138‑5p increased PC12 cell viability, inhibited cell apoptosis and attenuated proinflammatory responses, which may result in amelioration of SCI. However, all these effects were reversed by SIRT1 knockdown. Finally, it was observed that miR‑138‑5p altered the related protein expression of the PTEN/AKT pathway. These results indicated that miR‑138‑5p could regulate inflammatory responses and cell apoptosis in SCI models by modulating the PTEN/AKT signaling pathway via SIRT1, thus playing an important role in the development of SCI. Collectively, the present study demonstrated that miR‑138‑5p may be a novel therapeutic target for the treatment of SCI.

The distant metastasis in papillary thyroid carcinoma (PTC) is a major threat for PTC patients. Moreover, the involvement of long noncoding RNAs (lncRNAs) in the regulation of PTC progression has been extensively investigated. The aim of this study was to underscore whether lncRNA RP11-476D10.1 affects the proliferation, apoptosis and autophagy of PTC cells. Initially, we determined that lncRNA RP11-476D10.1 and LRRK2 were highly expressed in PTC cells. Meanwhile, through experimentation, miR-138-5p was confirmed to bind with lncRNA RP11-476D10.1 and LRRK2. It was also revealed that lncRNA RP11-476D10.1 downregulated the miR-138-5p expression, thereby upregulating the LRRK2 expression. After that, PTC cells were transfected with siRNA against RP11-476D10.1, or inhibitor or mimic of miR-138-5p to evaluate the influence of lncRNA RP11-476D10.1 on the PTC cell proliferation, apoptosis, and autophagy in vitro and on the tumor formation ability in vivo. The results showed that silenced lncRNA RP11-476D10.1 or overexpressed miR-138-5p enhanced the apoptosis and autophagy of PTC cells while reducing cell proliferation, with increased levels of Bax, LC3B, and Beclin1 and decreased Bcl-2 level were observed. The inhibitory role of silenced lncRNA RP11-476D10.1 role in the PTC development was further verified by the reduced tumor formation ability in nude mice. Our results demonstrated that lncRNA RP11-476D10.1 could bind to miR-138-5p and promote LRRK2 expression. Moreover, the silencing of lncRNA RP11-476D10.1 may inhibit the development of PTC, highlighting a novel insight for the development of superior therapeutic targets for PTC treatment., (© 2019 Wiley Periodicals, Inc.)

Background: MiR-138-5p is regarded as a tumour suppressor in many cancers. Transforming growth factor beta (TGF-β) often acts as a tumor promotor at the late stages of human cancers. However, the function of miR-138-5p on lung adenocarcinoma cells induced by TGF-β remains to be further confirmed., Methods: RT-qPCR was used to detect the expression of human lung adenocarcinoma tissues, adjacent normal tissues, and relative cell lines. When the lung adenocarcinoma cells A549 and H1299 were transfected with negative control (NC), miR-138-5p mimics and miR-138-5p inhibitor by lipofectamine3000 and treated with or without TGF-β1, the lung adenocarcinoma cell function was detected by Immunofluorescence, Western blotting (WB), cell counting Kit-8 (CCK8), colony formation, EdU, Wound-healing and Transwell assays. The relation between miR-138-5p and zinc finger E-box-binding homeobox 2 (ZEB2) was detected by RT-qPCR, WB, and Luciferase reporter assays. When ZEB2 was knocked down, the lung adenocarcinoma cell function was detected by WB, CCK8 and Transwell assays., Results: The expression of miR-138-5p was decreased in lung adenocarcinoma tissues and cell lines. When treated with or without TGF-β1, overexpression of miR-138-5p suppressed EMT, proliferation and metastasis of A549 and H1299. ZEB2 was verified as the direct target of miR-138-5p. Downregulation of ZEB2 suppressed EMT, proliferation and metastasis of lung adenocarcinoma cell, which could be reversed by miR-138-5p inhibitor., Conclusions: MiR-138-5p inhibits epithelial-mesenchymal transition, growth and metastasis of lung adenocarcinoma cells through targeting ZEB2., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

The mechanism of manganism caused by manganese (Mn), an important environmental risk factor for Parkinson's disease, is still unclear. Recent evidence suggested that autophagy participated in neurodegenerative diseases, in which microRNA played a crucial role. However, roles of microRNA in the aberrant autophagy that occurs in neurodegenerative diseases remains controversial. In nervous system, miRNA-138-5p is highly expressed and plays a key role in regulating memory and axon regeneration. Importantly, we also found that miR-138-5p expression decreased significantly after SH-SY5Y cells exposed to manganese chloride (MnCl 2 ) in previous study. To explore the role of miR-138-5p in Mn-induced autophagy, autophagy associated indicators were detected. And we found that MnCl 2 could induce autophagic dysregulation and inhibit expression of miR-138-5p. While the levels of LC3-II/LC3-I, Beclin1, and p62, the number of autophagosome formation significantly decreased after miR-138-5p over-expression, which demonstrated that miR-138-5p could clearly retard Mn-induced autophagy. In additional, we found there were classical and evolutionarily conserved miR-138-5p binding sites in 3'-UTR region of SIRT1, which was inhibited when overexpression of miR-138-5p. Therefore, it was speculated that elevated expression of SIRT1 may be resulted from inhibition of miR-138-5p after cells exposed to MnCl 2 . Finally, we found that SIRT1 inhibitor EX-527 suppressed Mn-induced autophagy as well as miR-138-5p, while the suppression was reversed by SIRT1-specific activator SRT1720. These results indicated that overexpression of miR-138-5p suppressed Mn-induced autophagy by targeting SIRT1., (© 2019 Wiley Periodicals, Inc.)