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Hepatocellular carcinoma (HCC) is a highly aggressive liver cancer with limited therapeutic options, and enhancing radiosensitivity remains a key challenge in improving treatment outcomes. Quercetin (Que) can inhibit the progression of hepatocellular carcinoma (HCC); however, its effect on HCC radiosensitivity remains unclear. This research investigates the role of Que in regulating HCC growth and radiosensitivity, aiming to provide a scientific foundation for enhancing the clinical efficacy of radiation therapy in HCC. The CCK-8 assay was used to determine the optimal treatment conditions for Que and X-rays. Changes in cell growth, cycle arrest, invasion, migration, the relative proportion of JC-1 red and green fluorescence (mitochondrial membrane potential), and the levels of ROS, MDA, SOD, and GSH-Px (oxidative stress) were assessed using flow cytometry, Transwell assays, JC-1 staining, Western blot, and ELISA, respectively, under Que, X-ray, and co-treatment conditions. The effect of miR-216a-3p knockdown on the action of Que was also explored, and the potential pathways by which Que regulates HCC growth and radiosensitivity were investigated in conjunction with in vivo subcutaneous transplantation tumor experiments. The in vitro treatment parameters for Que and X-rays were 100 µM and 4 Gy. Que combined with X-ray therapy enhanced HCC cell radiosensitivity, reduced proliferation, invasion, and migration, and promoted oxidative stress and apoptosis. Que was found to upregulate miR-216a-3p in HCC cells. Rescue experiments with miR-216a-3p knockdowns demonstrated that Que regulates HCC cell radiosensitivity via miR-216a-3p. In vivo research further showed that Que increased tumor sensitivity to X-rays by upregulating miR-216a-3p, thereby inhibiting HCC growth. In conclusion, Que has been shown to enhance HCC radiosensitization by upregulating miR-216a-3p and inhibiting HCC progression. Que may be a promising agent for increasing the radiosensitivity of HCC.

Clear cell renal cell carcinoma (ccRCC) is the most representative subtype of renal cancer, with a highly aggressive phenotype and extremely poor prognosis. Immune escape is one of the main reasons for ccRCC growth and metastasis, in which circular RNAs (circRNAs) play critical roles. Therefore, this research studied circAGAP1-associated mechanisms in immune escape and distant metastasis in ccRCC. circAGAP1/miR-216a-3p/MKNK2 was overexpressed or down-regulated by cell transfection. EdU assay, colony formation assay, scratch assay, Transwell assay, immunoblotting, and flow cytometry were used to evaluate cell proliferation, migration, invasion, EMT, and immune escape, respectively. Dual-luciferase reporting assay and RIP assay were used to evaluate the targeting relationship between circAGAP1/miR-216a-3p/MKNK2. Xenotransplantation in nude mice was used to evaluate the growth of ccRCC tumors in vivo. Here, circAGAP1 high expression was positively correlated with higher histological grade and distant metastasis and was a prognostic indicator for ccRCC. Depleting circAGAP1 effectively hampered the proliferative, invasive, and migratory capacities, EMT, and immune escape of ccRCC cells. Correspondingly, silencing circAGAP1 delayed tumor growth, distant metastasis, and immune escape in vivo. Mechanistically, circAGAP1 sponged the tumor suppressor miR-216a-3p, thereby preventing miR-216a-3p from inhibiting MAPK2. Collectively, our findings demonstrate that circAGAP1 exerts a tumor suppressor function through miR-216a-3p/MKNK2 during the immune escape and distant metastasis in ccRCC, and suggest that circAGAP1 may be a novel prognostic marker and therapeutic target for ccRCC. [ABSTRACT FROM AUTHOR]

Dual‐specificity phosphatase 5 (DUSP5) is a novel anti‐inflammatory modulator in many inflammatory diseases. However, the role of DUSP5 in fibroblast‐like synoviocytes (FLS) of rheumatoid arthritis (RA) remains unknown. In this study, we aimed to explore the biological function and regulation of DUSP5 in FLS. We found that lower DUSP5 expression level was detected in collagen‐induced arthritis (CIA) and synoviocyte MH7A. Overexpression of DUSP5 markedly decreased the proliferation, migration, and invasion of MH7A, which correlated with suppressing the phosphorylation of extracellular signal‐regulated kinase (ERK). Moreover, DUSP5 was identified as a novel target gene of miR‐216a‐3p, which was upregulated in FLS. Therefore, DUSP5 expression was negatively regulated by miR‐216a‐3p, and the effect of DUSP5 overexpression on FLS was reversed by miR‐216a‐3p mimics. Overall, our study demonstrates that DUSP5 is a miR‐216a‐3p target gene and its anti‐inflammatory function in FLS via inactivation of ERK. These results revealed that the miR‐216a‐3p/DUSP5 pathway may play a crucial role in the malignant behavior of FLS, which may serve as a new target for the treatment of RA. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms (SNPs) was associated with altering the secondary structure of long non-coding RNA (lncRNA). Increasing reports showed that lnc-LAMC2-1:1 SNP played an important role in cancer development and invasion. This study is to elucidate the molecular function of lnc-LAMC2-1:1 SNP rs2147578 promoting tumor progression in colon adenocarcinoma (COAD). In this study, we found that the lnc-LAMC2-1:1 SNP rs2147578 was upregulated in COAD cell lines. Furthermore, lnc-LAMC2-1:1 SNP rs2147578 promoted colon cancer migration, invasion, and proliferation. Interestingly, lnc-LAMC2-1:1 SNP rs2147578 positively regulated HMGB3 expression via miR-216a-3p in colon cancer cells. Functional enrichment analysis showed that targeting genes of miR-216a-3p were enriched in regulating the pluripotency of stem cells, MAPK signaling pathway, TNF signaling pathway, neurotrophin signaling pathway, relaxin signaling pathway, and FoxO signaling pathway. Tumor Immune Estimation Resource (TIMER) database revealed that there was a significantly positive correlation between HMGB3 expression and the infiltration of CD8+ T cells, B cells, neutrophils, macrophages, and CD4+ T cells. Finally, HMGB3 overexpression was validated in external data. In conclusions, lnc-LAMC2-1:1 SNP rs2147578 was involved in promoting COAD progression by targeting miR-216a-3p/HMGB3, and this study will provide a novel molecular target for COAD.

Abstract Background Abnormal proliferation and migration of human airway smooth muscle cells (HASMCs) play an important role in the development of childhood asthma. Long non-coding RNAs (lncRNAs) have been demonstrated to participate in HASMC proliferation and migration. We aimed to explore more effects and molecular mechanism of taurine upregulated gene 1 (TUG1) in childhood asthma. Results TUG1 and SMURF2 were overexpressed and miR-216a-3p was downregulated in childhood asthma patients and PDGF-BB-stimulated HASMCs. TUG1 knockdown attenuated PDGF-BB-triggered proliferation and migration of HASMCs. MiR-216a-3p was targeted by TUG1, and miR-216a-3p suppression counteracted the repressive effects of TUG1 interference on proliferation and migration in PDGF-BB-treated HASMCs. SMURF2 was a downstream target of miR-216a-3p, and SMURF2 upregulation abated the inhibiting effects of miR-216a-3p on migration and proliferation in PDGF-BB-exposed HASMCs. TUG1 sponged miR-216a-3p to positively regulate SMURF2 expression. Conclusion TUG1 downregulation inhibited PDGF-BB-induced HASMC proliferation and migration by regulating miR-216a-3p/SMURF2 axis, offering novel insight into the potential application of TUG1 for childhood asthma treatment.

Lihua Chang,1 Liang Kan2 1Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of China; 2Department of Gerontology and Geriatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of ChinaCorrespondence: Liang KanDepartment of Gerontology and Geriatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of ChinaEmail kanliang31cmu@163.comBackground: Rheumatoid arthritis (RA) is a chronic autoimmune disease of articular joint damage and elevated synovial hyperplasia. Abnormal proliferation, invasion inflammatory response of rheumatoid fibroblast-like synoviocytes (RA-FLS) play a critical role in RA progression. Mesenchymal stem cell (MSC)–derived exosomal circular RNAs are promising therapeutic manner for disease treatment. This work aimed to decipher the role of exosomal circFBXW7 in RA.Methods: The expression of circFBXW7, miR-216a-3p, and HDAC4 were detected in clinical RA samples. The RA rat model was established. Isolation and identification of exosomes from MSCs was conducted. The effects of exosomal circFBXW7 on RA was evaluated by qPCR, CCK-8, transwell assays, flow cytometry, Western blotting, ELISA, and immunohistochemical assay. Interaction between miR-216a-3p and circFBXW7 or HDAC4 was determined by luciferase reporter gene assay and RNA pulldown.Results: Exosomal circFBXW7 treatment suppressed proliferation, migration and inflammatory response of RA-FLSs and damage of RA model. CircFBXW7 could directly sponge miR-216a-3p to upregulate the expression of HDAC4. Inhibition of HDAC4 or upregulation of miR-216a-3p abolished the therapeutic function of exosomal circFBXW7. Our data demonstrated that circFBXW7 and HDAC4 were decreased, and miR-216a-3p was elevated in clinical RA sample compared with healthy samples.Conclusion: We concluded that MSC-derived exosomal circFBXW7 suppressed proliferation, migration and inflammatory response of RA-FLSs and damage of RA rats via sponging miR-216a-3p and release the activation of HDAC4. These findings may provide a novel therapeutic target for RA.Keywords: rheumatoid arthritis, mesenchymal stem cell, fibroblast-like synoviocytes, circFBXW7, miR-216a-3p, HDAC4

Background: Abnormal proliferation and migration of human airway smooth muscle cells (HASMCs) play an important role in the development of childhood asthma. Long non-coding RNAs (lncRNAs) have been demonstrated to participate in HASMC proliferation and migration. We aimed to explore more effects and molecular mechanism of taurine upregulated gene 1 (TUG1) in childhood asthma. Results: TUG1 and SMURF2 were overexpressed and miR-216a-3p was downregulated in childhood asthma patients and PDGF-BB-stimulated HASMCs. TUG1 knockdown attenuated PDGF-BB-triggered proliferation and migration of HASMCs. MiR-216a-3p was targeted by TUG1, and miR-216a-3p suppression counteracted the repressive effects of TUG1 interference on proliferation and migration in PDGF-BB-treated HASMCs. SMURF2 was a downstream target of miR-216a-3p, and SMURF2 upregulation abated the inhibiting effects of miR-216a-3p on migration and proliferation in PDGF-BB-exposed HASMCs. TUG1 sponged miR-216a-3p to positively regulate SMURF2 expression. Conclusion: TUG1 downregulation inhibited PDGF-BB-induced HASMC proliferation and migration by regulating miR-216a-3p/SMURF2 axis, offering novel insight into the potential application of TUG1 for childhood asthma treatment. [ABSTRACT FROM AUTHOR]

This study was designed to illustrate the function and role of PCAT1 in CCA. The relative expression was confirmed by RT-qPCR and western blot. The biological function of PCAT1 was evaluated by CCK8, EdU, colony formation, wound healing, transwell, and subcutaneous tumor formation assays. Protein levels of EMT markers were measured by western blot. The binding relationship was predicted by JASPAR and starBase. The binding of YY1 to PCAT1 promoter was assessed by ChIP and luciferase reporter. The binding capacity between miR-216a-3p and PCAT1 as well as BCL3 was assessed by luciferase reporter and AGO2-RIP assays. In this study, we found that PCAT1 was up-regulated in CCA tissues and cells, and the PCAT1 overexpression was associated with poor prognosis. Moreover, PCAT1 was assessed as an independent risk factor of prognosis for CCA patients. Amplified PCAT1 was found to promote tumor proliferation, migration, invasion and EMT process, whereas PCAT1 knockdown inhibited these malignant phenotypes. Mechanistically, PCAT1 was predominantly localized in the cytoplasm and competitively bound miR-216a-3p to increase BCL3 expression. In addition, PCAT1 was activated by transcription factor YY1. This study revealed that PCAT1 acted as an oncogene in CCA, and the YY1/PCAT1/miR-216a-3p/BCL3 axis exhibited critical functions in CCA progression. [ABSTRACT FROM AUTHOR]

Background: The long noncoding RNA small nucleolar RNA host gene 1 (SNHG1) has been demonstrated to play a crucial role in the progression of esophageal squamous cell carcinoma (ESCC). The current study aims to explore the deeper molecular mechanisms of SNHG1 in ESCC. Methods: Fifty patients with ESCC were enrolled to assess overall survival. Quantitative real-time PCR was performed to measure the levels of SNHG1, miR-216a-3p, and TMBIM6 in ESCC cells. Functional assessments of SNHG1 on ESCC cells were conducted using CCK-8 assay, flow cytometry, and Transwell assays. Western blot was conducted to detect the protein levels of TMBIM6 and proapoptotic proteins (Calpain and Caspase-12). The interaction among SNHG1, miR-216a-3p, and TMBIM6 was assessed with luciferase reporter assays. Results: Our study revealed that SNHG1 was notably increased in both clinical ESCC samples and cellular lines. Upregulation of SNHG1 in ESCC tissues was indicative of poor overall survival. Functionally, SNHG1 knockdown significantly inhibited the proliferation, migration, and invasion while promoting apoptosis in ESCC cells. Mechanistically, SNHG1 functioned as a competing endogenous RNA by sequestering miR-216a-3p to modulate TMBIM6 levels in ESCC cells. Notably, inhibiting miR-216a-3p or restoring TMBIM6 reversed the inhibitory effect induced by SNHG1 knockdown in ESCC cells. Conclusions: We demonstrate for the first time that SNHG1 may act as a competing endogenous RNA and promote ESCC progression through the miR-216a-3p/TMBIM6 axis. This highlights the potential of SNHG1 as a target for ESCC treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The tumor‐suppressive role of microRNA‐216a‐3p (miR‐216a‐3p) has been evidenced in multiple tumors. Yet, the relevance of miR‐216a‐3p in cervical cancer remains undermined. The current study was designed to determine the expression and potential function of miR‐216a‐3p in cervical cancer. Expression of miR‐216a‐3p was markedly decreased in cervical cancer and functional assays revealed an inhibitory effect of miR‐216a‐3p on the proliferation, colony formation, and invasion of cervical cancer. Actin‐like 6A (ACTL6A) was identified as a target gene of miR‐216a‐3p. Elevated ACTL6A expression was detected in cervical cancer, and ACTL6A inhibition exhibited a tumor‐suppressive effect. ACTL6A inhibition increased yes‐associated protein (YAP) phosphorylation and downregulated YAP‐mediated transcriptional activity. ACTL6A restoration or YAP reactivation partially abrogated the miR‐216a‐3p‐mediated antitumor effect in cervical cancer cells. Taken together, these data demonstrate that miR‐216a‐3p acts as a potential tumor‐suppressive miRNA in cervical cancer, which exerts its function through inhibition of YAP signaling via targeting ACTL6A. [ABSTRACT FROM AUTHOR]

Effect of miR-216a-3p on lung cancer hasn't been investigated. Here, we explored its effects on lung cancer. MiR-216a-3p expression in lung cancer tissues and cells was detected by RT-qPCR. The target gene of miR-216a-3p was predicted by bioinformatics and confirmed by luciferase-reporter assay. After transfection, cell viability, migration, invasion, proliferation, and apoptosis were detected by MTT, scratch, transwell, colony formation, and flow cytometry. The expressions of COPB2 and apoptosis-related factors were detected by RT-qPCR or western blot. MiR-216a-3p was low-expressed and COPB2 was high-expressed in lung cancer tissues and cells. MiR-216a-3p targeted COPB2 and regulated its expression. MiR-216a-3p inhibited lung cancer cell viability, migration, invasion, and proliferation, while promoted apoptosis. Effect of miR-216a-3p on lung cancer was reversed by COPB2. MiR-216a-3p regulated proliferation, apoptosis, migration, and invasion of lung cancer cells via targeting COPB2. MiR-216a-3p inhibits the proliferation, migration, and invasion of lung cancer cells via targeting COPB2. [ABSTRACT FROM AUTHOR]

Limonin has been shown to exert anti-inflammatory effects, however, its roles in tumor progression remain unclear. This work aims to investigate the roles and related mechanism of limonin in the stemness of breast cancer cells. Here, we found that limonin attenuated the stemness of breast cancer cells in a concentration-dependent manner, evident by the decreasing the capacity of cell spheroid formation, expression of stemness markers and ALDH1 activity, whereas had no toxicity on non-tumorigenic cells. Additionally, limonin enhanced adriamycin sensitivity of breast cancer cells and attenuated adriamycin resistance in adriamycin-resistant breast cancer cells. Mechanistically, limonin decreased MIR216A methylation level and thus increased miR-216a-3p expression. Furthermore, miR-216a-3p could directly bind to WNT3A and thus inactivated Wnt/β-catenin pathway. Therefore, our results indicate that limonin could attenuate the stemness and chemoresistance via inhibiting MIR216A methylation and subsequently suppressing Wnt/β-catenin pathway.

OBJECTIVE: To explore whether miR-216a-3p could promote differentiation of bone marrow mesenchymal stem cells (BMMSCs) into type II alveolar epithelial cells (ACE II) via Wnt/β-catenin pathway, thereby alleviating neonatal respiratory distress syndrome (NRDS). MATERIALS AND METHODS: BMMSCs were directionally differentiated into ACE II cells. Expressions of ACE II cell-specific transcription factors Occludin, KGF, CK18, SpA, SpB, and SpC were detected at the different time points after cell differentiation. Enzyme-linked immunosorbent assay (ELISA) was applied to detect inflammatory factors in the culture medium, including interleukin-1 (IL-1), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and Interferon-α (INF-α). After overexpression or knockdown of miR-216a-3p in BMMSCs, expressions of ACE II cell-specific transcription factors and inflammatory factors were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot. Rescue experiments were carried out after DKK-1 treatment in BMMSCs. RESULTS: Expressions of ACE II cell-specific transcription factors Occludin, KGF, CK18, SpA, SpB, and SpC were elevated with the prolongation of cell differentiation. Overexpression of miR-216a-3p elevated levels of pro-inflammatory factors (IL-1, TNF-α, and INF-α) and reduced anti-inflammatory factor (IL-10). Expressions of ACE II cell-specific transcription factors Occludin, KGF, CK18, SpA, SpB, and SpC were remarkably increased at 7 d and 14 d compared to those detected at 1 d. Overexpression of miR-216a-3p in BMMSCs downregulated Wnt3a expression. The regulatory effect of miR-216a-3p on BMMSCs differentiation was partially reversed by DKK-1 treatment. CONCLUSIONS: Knockdown of miR-216a-3p induces differentiation of BMMSCs into ACE II cells through Wnt/β-catenin pathway, thereby alleviating NRDS. [ABSTRACT FROM AUTHOR]

This work aims to elucidate the effects and the potential underlying mechanisms of microRNA-216a-3p (miR- 216a-3p) on the proliferation, migration, and invasion of gastric cancer (GC) cells. In this study, we revealed that the expression of miR-216a-3p was significantly elevated in GC tissues and cell lines. The different expression level of miR-216a-3p was firmly correlated with clinicopathological characteristics of GC patients. We next demonstrated that upregulation of miR-216a-3p could dramatically promote the ability of proliferation, migration, and invasion of GC cells using a series of experiments, whereas downregulation essentially inhibited these properties. Additionally, through bioinformatics analysis and biological approaches, we confirmed that runt-related transcription factor 1 (RUNX1) was a direct target of miR-216a-3p, and overexpression of RUNX1 could reverse the potential effect of miR-216a-3p on GC cells. Furthermore, mechanistic investigation using Western blot analysis showed that downregulation of RUNX1 by miR-216a-3p could stimulate the activation of NF-κB signaling pathway. In summary, this work proved that miR-216a-3p can promote GC cell proliferation, migration, and invasion via targeting RUNX1 and activating the NF-κB signaling pathway. Therefore, miR-216a-3p/RUNX1 could be a possible molecular target for innovative therapeutic agents against GC. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms (SNPs) was associated with altering the secondary structure of long non-coding RNA (lncRNA). Increasing reports showed that lnc-LAMC2-1:1 SNP played an important role in cancer development and invasion. This study is to elucidate the molecular function of lnc-LAMC2-1:1 SNP rs2147578 promoting tumor progression in colon adenocarcinoma (COAD). In this study, we found that the lnc-LAMC2-1:1 SNP rs2147578 was upregulated in COAD cell lines. Furthermore, lnc-LAMC2-1:1 SNP rs2147578 promoted colon cancer migration, invasion, and proliferation. Interestingly, lnc-LAMC2-1:1 SNP rs2147578 positively regulated HMGB3 expression via miR-216a-3p in colon cancer cells. Functional enrichment analysis showed that targeting genes of m iR-216a-3p were enriched in regulating the pluripotency of stem cells, MAPK signaling pathway, TNF signaling pathway, neurotrophin signaling pathway, relaxin signaling pathway, and FoxO signaling pathway. Tumor Immune Estimation Resource (TIMER) database revealed that there was a significantly positive correlation between HMGB3 expression and the infiltration of CD8 + T cells, B cells, neutrophils, macrophages, and CD4 + T cells. Finally, HMGB3 overexpression was validated in external data. In conclusions, lnc-LAMC2-1:1 SNP rs2147578 was involved in promoting COAD progression by targeting miR-216a-3p/HMGB3 , and this study will provide a novel molecular target for COAD., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Recent studies have shown that circular RNA circFLNA is abnormally expressed in a variety of malignant tumors, but its role and mechanism in bladder carcinoma (BCa) are still unclear. The present paper aims to contribute to research on the effects and mechanism of circFLNA on the malignant phenotype of BCa. In this study, the expressions of circFLNA, miR-216a-3p and BTG2 in BCa and BCa cells (EJ, T24, 5637, TCC-SUP) were detected by qRT-PCR. EdU staining, colony formation, Transwell assay, wound healing assays, and sphere formation assay were used to measure the cell proliferation, viability, invasion, migration, and cell stemness of BCa cells after circFLNA overexpression. In addition, the correlation existed between miR-216a-3p and circFLNA or BTG2 was confirmed by Dual-Luciferase Reporter assay and RNA pull-down. Western blot was utilized to determine the expression of BTG2, MMP2, epithelial-mesenchymal transition (EMT)-related proteins (vimentin, E-cadherin) and stem cell-specific proteins (CD34, OCT4, SOX2). Our study confirmed that downregulated circFLNA and BTG2 expression and upregulated miR-216a-3p were found in both BCa tissues and cell lines. Meanwhile, upregulated circFLNA inhibited proliferation, invasion and migration, EMT and stemness of BCa cells. MiR-216a-3p was a target gene of circFLNA and could target BTG2. Further analysis finally demonstrated that circFLNA sponged miR-216a-3p and indirectly promoted BTG2 expression, ultimately regulating proliferation, migration, invasion and EMT of BCa cells. In conclusion, circFLNA inhibits the malignant phenotype of BCa cells and their stemness through miR-216a-3p/BTG2, thus suppressing BCa progression.

Background: Parkinson's disease (PD) is a common central nervous system degenerative disease in middle-aged and elderly people. Our study aimed to illuminate the relationship and mechanism of long-chain non-coding RNA SNHG1 and miRNA (miR)-216a-3p in PD., Methods: Human neuroblastoma cell lines were treated with MPP + to construct a PD model. Real-time fluorescent quantitative PCR was used to detect the cellular expression of SNHG1. Neuronal cell activity and apoptosis were compared before and after SNHG1 knock-down, as was neuronal miR-216a-3p expression. Further, a luciferase reporter gene experiment was performed to verify BAX as the target of miR-216a-3p. Anti-miR-216a-3p and BAX were co-transfected into PD model cells, and neuronal cellular activity and apoptosis were observed. Finally, the potential regulatory network of SNHG1/miR-216a-3p/BAX in PD was investigated., Results: The expression of miR-216a-3p was decreased in the PD model cells, and re-expression reversed the high apoptotic rate and cell vitality inhibition in PD model cells. SNHG1 interacted with miR-216a-3p and negatively regulated its upstream molecules, while miR-216a-3p attenuated the effect of SNHG1 knock-down on neurons. The overexpression of BAX in the PD cell model blocked the damage by miR-216a-3p to neurons. At the same time, SNHG1 acted as a coordinator, mediating the regulation of BAX via miR-216a-3p, thereby affecting the activity and apoptotic rate of neurons in the PD model., Conclusions: SNHG1 interacts with miR-216a-3p to regulate the expression of BAX. This SNHG1/miR-216a-3p/BAX molecular regulatory network is implicated in the pathogenesis of PD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-21-1613). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

This study was designed to illustrate the function and role of PCAT1 in CCA. The relative expression was confirmed by RT-qPCR and western blot. The biological function of PCAT1 was evaluated by CCK8, EdU, colony formation, wound healing, transwell, and subcutaneous tumor formation assays. Protein levels of EMT markers were measured by western blot. The binding relationship was predicted by JASPAR and starBase. The binding of YY1 to PCAT1 promoter was assessed by ChIP and luciferase reporter. The binding capacity between miR-216a-3p and PCAT1 as well as BCL3 was assessed by luciferase reporter and AGO2-RIP assays. In this study, we found that PCAT1 was up-regulated in CCA tissues and cells, and the PCAT1 overexpression was associated with poor prognosis. Moreover, PCAT1 was assessed as an independent risk factor of prognosis for CCA patients. Amplified PCAT1 was found to promote tumor proliferation, migration, invasion and EMT process, whereas PCAT1 knockdown inhibited these malignant phenotypes. Mechanistically, PCAT1 was predominantly localized in the cytoplasm and competitively bound miR-216a-3p to increase BCL3 expression. In addition, PCAT1 was activated by transcription factor YY1. This study revealed that PCAT1 acted as an oncogene in CCA, and the YY1/PCAT1/miR-216a-3p/BCL3 axis exhibited critical functions in CCA progression., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

We investigated MAPK14-dependent resistance to sorafenib in hepatocellular carcinoma (HCC). Bioinformatics analysis and dual luciferase reporter assays in HCC cell lines showed that miR-216a-3p directly binds to the 3'UTR of MAPK14 mRNA and downregulates MAPK14 protein expression. Consequently, miR-216a-3p expression correlates inversely with MAPK14 protein levels in HCC patient tissues. miR-216a-3p overexpression significantly increases the sorafenib sensitivity of HCC cells by suppressing MAPK14 expression and reducing the subsequent activation of the MEK/ERK and ATF2 signaling pathways. The growth of xenograft tumors derived from miR-216a-3p-overexpression HCC cells was significantly diminished in sorafenib-treated Balb/c nude mice compared to controls. High miR-216a-3p levels in HCC tissue samples prior to treatment correlated with a better sorafenib response and favorable prognosis. Our findings thus demonstrate that miR-216a-3p enhances sorafenib sensitivity in HCC cells and tumor tissues by decreasing MAPK14 levels, thereby inhibiting the MAPK14-dependent MEK/ERK and ATF2 signaling.

Background: Lung adenocarcinoma is a non-small cell lung cancer with a high mortality. There is little published data on the role of coatomer protein complex subunit β (COPB2) in lung adenocarcinoma. The current study aimed to explore the effects of COPB2 on lung adenocarcinoma cells., Methods: The differential expression of COPB2 in normal cells and lung adenocarcinoma cells was detected by quantitative real time-polymerase chain reaction (qRT-PCR) and Western blotting. Then, cell viability assay, flow cytometry and Transwell experiments were performed to study the effects of COPB2 on cell growth, apoptosis, migration and invasion. MiRNA targeting COPB2 was predicted by TargetScan and validated by luciferase assay, qRT-PCR and Western blotting. The effects of miRNA inhibitor on siCOPB2 were analyzed by rescue experiments. Finally, apoptosis and metastatic marker proteins were detected by Western blotting., Results: COPB2 was high-expressed in lung adenocarcinoma cells. Silencing COPB2 inhibited cell viability and cell metastasis, and significantly increased apoptosis. MiR-216a-3p was predicted to be able to target COBP2. Rescue experiment showed that miR-216a-3p inhibitor promoted cell viability, migration and invasion, and inhibited apoptosis of lung adenocarcinoma cells, partly reversed the effects of siCOPB2. Moreover, Western blotting showed that siCOPB2 up-regulated expressions of cleaved Caspase-3, Caspase-3, BCL2 associated X (Bax), and E-Cadherin, and down-regulated expressions of BCL2 apoptosis regulator (Bcl-2), N-Cadherin, and Vimentin, and the above effects were also partly reversed by miR-216a-3p inhibitor., Conclusions: High-expressed COPB2 promotes metastasis and inhibits apoptosis of lung adenocarcinoma cells through functioning as a target of miR-216a-3p., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2020.02.65). The authors have no conflicts of interest to declare., (2020 Translational Cancer Research. All rights reserved.)

Limonin has been shown to exert anti-inflammatory effects, however, its roles in tumor progression remain unclear. This work aims to investigate the roles and related mechanism of limonin in the stemness of breast cancer cells. Here, we found that limonin attenuated the stemness of breast cancer cells in a concentration-dependent manner, evident by the decreasing the capacity of cell spheroid formation, expression of stemness markers and ALDH1 activity, whereas had no toxicity on non-tumorigenic cells. Additionally, limonin enhanced adriamycin sensitivity of breast cancer cells and attenuated adriamycin resistance in adriamycin-resistant breast cancer cells. Mechanistically, limonin decreased MIR216A methylation level and thus increased miR-216a-3p expression. Furthermore, miR-216a-3p could directly bind to WNT3A and thus inactivated Wnt/β-catenin pathway. Therefore, our results indicate that limonin could attenuate the stemness and chemoresistance via inhibiting MIR216A methylation and subsequently suppressing Wnt/β-catenin pathway., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Colorectal Cancer (CRC) is a most common digestive system malignant tumor. Despite recent advance in CRC treatment, searching for efficient biomarker and individual treatment therapy remains an urgent need. Cyclooxygenase-2 (COX-2) plays a critical role in the development and progression of CRC. In addition, shunting of arachidonic acid metabolism to the 5-lipoxygenase (ALOX5, 5-LO) pathway has also been reported to be implicated in the CRC pathogenesis. Cancer cell viability is promoted by ALOX5 through several mechanisms that are similar to those of COX-2. In recent years, it has been widely recognized that through inhibition of target genes, miRNAs can exert both oncogenic and tumor suppressive functions, depending on circumstances. In the present study, we screened for candidate microRNAs (miRNAs) which were predicted to regulate COX-2 and ALOX5 by online tools. Among the candidate miRNAs, miR-216a-3p expression was down-regulated in CRC tissues and cell lines; a higher miR-216a-3p expression was correlated with longer overall survival in patients with CRC. Moreover, ectopic miR-216a-3p expression significantly suppressed CRC cell proliferation. Using luciferase reporter gene, real-time PCR, and western blot assays, we confirmed the miR-216a-3p regulation of COX-2 and ALOX5 through direct targeting; further verified that miR-216a-3p could inhibit COX-2 and ALOX5 expression in CRC cells, thus to affect CRC cell proliferation. Taken together, miR-216a-3p presents a novel target of CRC treatment; rescuing miR-216a-3p expression in CRC might be a promising strategy for CRC treatment., (© 2017 Wiley Periodicals, Inc.)