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Abstract Objective Gastric cancer (GC) remains a prevailing threat to life. Baicalein exhibits anti-cancer properties. This study estimated the mechanism of baicalein in GC cell apoptosis by mediating endoplasmic reticulum stress (ERS) through the PI3K/AKT pathway. Methods After treatment with different concentrations of baicalein, GC cell (HGC-27 and AGS) viability was detected by MTT assay. AGS cells more sensitive to baicalein treatment were selected as study subjects. The IC50 of baicalein on AGS cells was determined. Colony formation, cell cycle, and apoptosis were detected using crystal violet staining and flow cytometry. Levels of ERS-related and BTG3/PI3K/AKT pathway-related proteins were determined by Western blot. Intracellular Ca2+ level was measured using Fluo-3 AM fluorescence working solution. GC mouse models were established by subcutaneously injecting AGS cells into the right rib and were intragastrically administrated with baicalein. Tumor volume and weight were recorded. Expression of Ki67 in tumor tissues and positive expression of apoptotic cells were detected by immunohistochemistry and TUNEL staining. Results Baicalein inhibited cell proliferation and induced G0/G1 arrest and apoptosis by regulating the cell cycle, and triggered ERS in GC cells. Baicalein impeded the PI3K/AKT pathway by activating BTG3, thereby triggering ERS and inducing apoptosis. BTG3 inhibition reversed baicalein-induced apoptosis and ERS. Baicalein regulated GC cells in a concentration-dependent manner. Moreover, in xenograft mice, baicalein prevented tumor growth, decreased Ki67-positive cells, activated BTG3, and inhibited the PI3K/AKT pathway, thus activating ERS and increasing apoptotic cells. Conclusion Baicalein facilitates GC cell apoptosis by triggering ERS via repression of the PI3K/AKT pathway.

Objective: Gastric cancer (GC) remains a prevailing threat to life. Baicalein exhibits anti-cancer properties. This study estimated the mechanism of baicalein in GC cell apoptosis by mediating endoplasmic reticulum stress (ERS) through the PI3K/AKT pathway. Methods: After treatment with different concentrations of baicalein, GC cell (HGC-27 and AGS) viability was detected by MTT assay. AGS cells more sensitive to baicalein treatment were selected as study subjects. The IC50 of baicalein on AGS cells was determined. Colony formation, cell cycle, and apoptosis were detected using crystal violet staining and flow cytometry. Levels of ERS-related and BTG3/PI3K/AKT pathway-related proteins were determined by Western blot. Intracellular Ca2+ level was measured using Fluo-3 AM fluorescence working solution. GC mouse models were established by subcutaneously injecting AGS cells into the right rib and were intragastrically administrated with baicalein. Tumor volume and weight were recorded. Expression of Ki67 in tumor tissues and positive expression of apoptotic cells were detected by immunohistochemistry and TUNEL staining. Results: Baicalein inhibited cell proliferation and induced G0/G1 arrest and apoptosis by regulating the cell cycle, and triggered ERS in GC cells. Baicalein impeded the PI3K/AKT pathway by activating BTG3, thereby triggering ERS and inducing apoptosis. BTG3 inhibition reversed baicalein-induced apoptosis and ERS. Baicalein regulated GC cells in a concentration-dependent manner. Moreover, in xenograft mice, baicalein prevented tumor growth, decreased Ki67-positive cells, activated BTG3, and inhibited the PI3K/AKT pathway, thus activating ERS and increasing apoptotic cells. Conclusion: Baicalein facilitates GC cell apoptosis by triggering ERS via repression of the PI3K/AKT pathway. [ABSTRACT FROM AUTHOR]

B cell transposition gene 3 (BTG3) is reported to be a tumor suppressor and suppresses proliferation and cell cycle progression. This study aims to analyze the clinicopathological and prognostic significances, and signal pathways of BTG3 mRNA expression in human beings through bioinformatics analysis. We analyzed BTG3 expression using Oncomine, TCGA (the cancer genome atlas), Xiantao, UALCAN (The University of ALabama at Birmingham Cancer data analysis Portal) and Kaplan-Meier plotter databases. Down-regulated BTG3 expression was observed in lung and breast cancers, compared with normal tissues (p < 0.05), but not for gastric and ovarian cancer (p < 0.05). The methylation of BTG3 was shown to be adversely correlated with its mRNA expression (p < 0.05). BTG3 expression was higher in gastric intestinal-type than diffuse-type carcinomas, G1 than G3 carcinomas (p < 0.05), in female than male cancer patients, T1-2 than T3-4, and adenocarcinoma than squamous cell carcinoma of lung cancer (p < 0.05), in invasive ductal than lobular carcinoma, N0 than N1 and N3, TNBC (triple-negative breast cancer) than luminal and Her2+, and Her2+ than luminal cancer of breast cancer (p < 0.05), and G3 than G2 ovarian carcinoma (p < 0.05). BTG3 expression was positively related to the survival rate of gastric and ovarian cancer patients (p < 0.05), but not for breast cancer (p < 0.05). KEGG and PPI (protein-protein interaction) analysis showed that the BTG3 was involved in cell cycle and DNA replication, digestion and absorption of fat and protein, spliceosome and ribosome in cancer. BTG3 expression was positively linked to carcinogenesis, histogenesis, and aggressive behaviors, and was employed to evaluate the prognosis of cancers by regulating cell cycle, metabolism, splicing and translation of RNA. [ABSTRACT FROM AUTHOR]

Abstract Background Although the neuroprotective role of propofol has been identified recently, the regulatory mechanism associated with microRNAs (miRNAs/miRs) in neuronal cells remains to be poorly understood. We aimed to explore the regulatory mechanism of propofol in hypoxia-injured rat pheochromocytoma (PC-12) cells. Methods PC-12 cells were exposed to hypoxia, and cell viability and apoptosis were assessed by CCK-8 assay and flow cytometry assay/Western blot analysis, respectively. Effects of propofol on hypoxia-injured cells were measured, and the expression of miR-153 was determined by stem-loop RT-PCR. After that, whether propofol affected PC-12 cells under hypoxia via miR-153 was verified, and the downstream protein of miR-153 as well as the involved signaling cascade was finally explored. Results Hypoxia-induced decrease of cell viability and increase of apoptosis were attenuated by propofol. Then, we found hypoxia exposure up-regulated miR-153 expression, and the level of miR-153 was further elevated by propofol in hypoxia-injured PC-12 cells. Following experiments showed miR-153 inhibition reversed the effects of propofol on hypoxia-treated PC-12 cells. Afterwards, we found BTG3 expression was negatively regulated by miR-153 expression, and BTG3 overexpression inhibited the mTOR pathway and AMPK activation. Besides, hypoxia inhibited the mTOR pathway and AMPK, and these inhibitory effects could be attenuated by propofol. Conclusion Propofol protected hypoxia-injured PC-12 cells through miR-153-mediataed down-regulation of BTG3. BTG3 could inhibit the mTOR pathway and AMPK activation.

Background/Aims: MicroRNAs have been validated to play a crucial role in tumorigenesis of non-small cell lung cancer (NSCLC). Although miR-106b-5p has been reported to play a vital role in various malignancies the physiological function of miR-106b-5p in NSCLC still remain unknown. In this study, we investigated the role of miR-106b-5p in NSCLC. Methods: Quantitative real-time polymerase chain reaction was conducted to estimate the expression of miR-106b-5p and BTG3 in both NSCLC tissues and cell lines. The effects of miR-106b-5p on proliferation were determined in vitro using CCK-8 proliferation assays, 5-ethynyl-2’-deoxyuridine (EdU) incorporation, colony formation assays and cell-cycle assays and the in vivo effects were evaluated by a mouse tumorigenicity model. Cell apoptosis and cell cycle was investigated by flow cytometric analysis in vitro. The molecular mechanism underlying the relevance between miR-106b-5p and BTG3 was confirmed by luciferase assay and western blot. Results: In current study, we found a relatively higher miR-106b-5p and lower BTG3 expression in NSCLC specimens and cell lines. BTG3 was verified as a direct target of miR-106b-5p by luciferase assay. In vitro, over-expression of miR-106b-5p promoted proliferation and inhibited apoptosis by down-regulating BTG3 expression. In vivo, miR-106b-5p promoted xenograft tumor formation. Conclusion: Our findings revealed for the first time that miR-106b-5p plays a tumorigenesis role in NSCLC progression by down-regulating BTG3 expression, which may lead to a novel insight to the potential biomarker and novel therapeutic strategies for NSCLC patients.

Abstract Background Epithelial–mesenchymal transition (EMT) and dysregulated microRNAs (miRNAs) have important roles in driving chemoresistance. We previously reported that iASPP is a key EMT inducer and could increase cisplatin resistance in cervical cancer (CC) cells. Herein, we investigate the downstream mechanisms through which iASPP contributes to EMT and cisplatin resistance in CC. Methods By using a lentiviral system, we investigated the effects of iASPP knockdown on CC cell growth and chemosensitivity of CC cells to cisplatin in vivo. We examined if miR-20a, which was up-regulated following iASPP overexpression, would influence metastatic phenotypes and cisplatin resistance in CC cells, and explored the possible molecular mechanisms involved. Results Knockdown of iASPP suppressed CC cell proliferation and sensitized CC cells to cisplatin in vivo. iASPP promotes miR-20a expression in a p53-dependent manner. Upregulation of miR-20a induced EMT and the recovery of CC cell invasion and cisplatin chemoresistance that was repressed by iASPP knockdown. We identified FBXL5 and BTG3 as two direct miR-20a targets. Silencing of FBXL5 and BTG3 restored cell invasion and cisplatin chemoresistance, which was suppressed by iASPP or miR-20a knockdown. Reduced FBXL5 and BTG3 expression was found in CC samples and associated with poor prognosis in CC patients. Conclusions iASPP promotes EMT and confers cisplatin resistance in CC via miR-20a-FBXL5/BTG3 signaling.

Tumor recurrence and metastasis after surgical resection are the major causes for the cancer-related death of hepatocellular carcinoma (HCC). Thus, better understanding the mechanisms involved in tumor progression will benefit to improve HCC treatment. Accumulating evidence demonstrates that microRNAs (miRNAs) play critical roles in the development and progression of HCC. However, the function of miR-519c-3p in HCC and its related mechanism remain unexplored. Here, we reported that miR-519c-3p was strongly overexpressed in HCC tissues, which was significantly correlated with poor prognosis and clinicopathological features including tumor size ≥5 cm, vascular invasion and advanced tumor-node-metastasis (TNM) stages (III + IV). Furthermore, the elevated levels of miR-519c-3p were observed in HCC cell lines. Subsequently, gain- or loss-of-function assays demonstrated that miR-519c-3p promoted HCC cell proliferation, migration as well as invasion in vitro, and facilitated the growth and metastasis of HCC cells in vivo. Mechanistically, B-cell translocation gene 3 (BTG3) was identified as a direct downstream target of miR-519c-3p. The level of BTG3 mRNA was downregulated in HCC and negatively correlated with miR-519c-3p expression. Western blotting confirmed that BTG3 was negatively regulated by miR-519c-3p in HCC cells. Luciferase reporter assays illustrated the direct interaction between miR-519c-3p and the 3′UTR of BTG3 mRNA. Recuse experiments demonstrated that BTG3 mediated the promoting effects of miR-519c-3p on the proliferation and motility of HCC cells. Collectively, our results suggest that miR-519c-3p functions as a tumor promotor in regulating the growth and metastasis of HCC by targeting BTG3, and potentially serves as a novel therapeutic target for HCC.

5-Fluorouracil (5-FU)-based chemotherapy has always been the first-line treatment of colorectal cancer (CRC). However, the occurrence of clinical 5-FU resistance is a major reason for CRC therapy failure. This study intended to explore the possible role of long non-coding RNA HOTAIRM1 (HOTAIRM1) in the pathogenesis of 5-FU resistant CRC and its underlying mechanism. Our data showed that HOTAIRM1 was downregulated in CRC tissues and cell lines (HCT116 and SW480), and even lower in 5-FU resistant CRC tissues and cell lines (HCT116/5-FU and SW480/5-FU). In vitro, effects of HOTAIRM1 dysregulation in 5-FU resistant CRC cells were investigated and its overexpression could reduce cell viability, invasion, migration, and multi-drug resistance as evidenced by MTT assay, Transwell assay, epithelial-mesenchymal transition (EMT), and western blot analyzing expression of drug-resistant genes MRP1 and MDR1, respectively. Mechanically, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) identified that HOTAIRM1 and B-cell translocation gene 3 (BTG3) were target genes of miR-17-5p. Moreover, miR-17-5p was upregulated and BTG3 was downregulated in HCT116/5-FU and SW480/5-FU cells. Silencing of miR-17-5p showed suppressive role on cell viability, invasion, migration, and multi-drug resistance in HCT116/5-FU and SW480/5-FU cells, which could be abolished by HOTAIRM1 knockdown. Similarly, ectopic expression of miR-17-5p reversed BTG3-mediated inhibition on cell viability, invasion, migration, and multi-drug resistance. In vivo, the tumorigenesis of HCT116/5-FU cells when highly expressed HOTAIRM1 by lentivirus infection was inhibited through downregulating miR-17-5p and upregulating BTG3. In conclusion, HOTAIRM1 might act as a tumor-suppressor in 5-FU resistant CRC cells in vitro and in vivo through downregulating miR-17-5p/BTG3 pathway and inhibiting multi-drug resistance.

A previous report has revealed that cucurbitacin B (CuB) inhibits cancer cell proliferation and tumorigenesis in non-small cell lung cancer (NSCLC) through epigenetic modifications of several genes. However, whether CuB regulates cell proliferation and apoptosis by altering methylation status of BTG3 in colorectal cancer (CRC) remains unknown. In the present study, the results showed that BTG3 was downregulated in CRC tissues compared with adjacent normal tissues. CuB significantly increased BTG3 levels, induced promoter demethylation, decreased the levels of DNA methyltransferases (DNMT1, DNMT3a and DNMT3b) in both CRC cell lines (SW480 and Caco-2) and the effects of CuB were comparable with those of 5-Aza-dC. We also found that CuB inhibited cell proliferation, accompanied with decreased expression of Ki67. Furthermore, CuB treatment induced cell cycle arrest at G1 phase in SW480 and Caco-2 cells, as well as decreased levels of Cyclin D1 and Cyclin E1. Incubation with CuB promoted cell apoptosis in both CRC cell lines in vitro, accompanied with elevation of cleaved caspase-3 and cleaved PARP. BTG3 knockdown abolished the effects of CuB in CRC cells. In summary, CuB-induced proliferation inhibition and cell apoptosis may be due to the reactivation of BTG3 by promoter demethylation. CuB may be a promising agent for CRC therapy. [ABSTRACT FROM AUTHOR]

This study explores the role of miR-93-5p in high-risk HPV-positive (HR-HPV) cervical cancer by targeting of BTG3. Cervical tissues were collected from 332 patients with conditions of chronic cervicitis (n = 42), low-grade cervical intraepithelial neoplasia (CIN I, n = 51), CIN II (n = 49), CIN III (n = 43), cervical cancer (n = 90), and normal cervical tissues (n = 57). HR-HPV DNA was detected by Hybrid Capture 2, and the expressions of miR-93-5p and BTG3 were determined by qRT-PCR and Western blot. The target relationship between miR-93-5p and BTG3 was verified by dual-luciferase reporter gene assay. HPV-positive cervical cancer cells (CaSki and HeLa) were divided into control, NC, inhibitor, BTG3, and mimic + BTG3 groups. CCK-8, Annexin V-APC/PI, and Transwell assays were applied to evaluate cell biological activities. MiR-93-5p was positively related but BTG3 was inversely related to HR-HPV infection. Additionally, miR-93-5p expression was negatively correlated with BTG3 expression in cervical cancer tissues infected with HR-HPV. HPV-positive cervical cancer cells showed higher miR-93-5p and lower BTG3 levels than negative cells. CaSki and HeLa cells in the inhibitor group showed increased BTG3 compared with the control group. After transfection with miR-93-5p inhibitor or BTG3 activation plasmid, proliferation and metastasis were inhibited, but apoptosis was promoted. The mimic + BTG3 group showed increased cell proliferation and metastasis but decreased cell apoptosis compared with the BTG3 group. Upregulated miR-93-5p was positively related but downregulated BTG3 was inversely related to HR-HPV infection, and inhibition of miR-93-5p may have blocked HPV-positive cervical cancer development by targeting of BTG3. [ABSTRACT FROM AUTHOR]

Neonatal brain hypoxia is a disease that affects the nervous system in children. Salidroside is a compound that has an anti-hypoxic effect, but the mechanism of salidroside in neonatal cerebral hypoxia is unclear. Hence, we investigated the regulatory effect and mechanism of salidroside on hypoxic-induced injury of neural stem cells (NSCs). NSCs derived from embryo 14 Sprague-Dawley rats were treated by hypoxia, followed by the treatment of 0.8 mM salidroside. The expression levels of miR-210 and BTG3 in NSCs were altered by transfection. Cell viability and apoptosis were examined by CCK-8 and flow cytometry analysis. qRT-PCR and Western blot were performed to assess the expression changes of miR-210, BTG3, apoptosis-related factors and core factors in PI3K/AKT/mTOR pathway. We found that hypoxia induced an apoptosis-dependent death in NSCs. Salidroside exerted bFGF-like effect, as it alleviated hypoxia-induced viability impairment and apoptosis in NSCs. Further studies showed that hypoxia plus salidroside elevated miR-210 expression, and the protective actions of salidroside on hypoxia-modulated death in NSCs were attenuated by miR-210 suppression, while were enhanced by miR-210 overexpression. Besides, BTG3 was negatively regulated by miR-210. Overexpression of BTG3 inhibited the activation of PI3K/AKT/mTOR signaling pathway; of contrast, suppression of BTG3 promoted it. To conclude, this study provide in vitro evidence that salidroside protected NSCs against hypoxia-induced injury by up-regulation of miR-210, which in turn inhibited the expression of BTG3 and activated PI3K/AKT/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Purpose: B-cell translocation gene 3 (BTG3) has been identified as a candidate driver gene for various cancers, but its specific role in colorectal cancer (CRC) is poorly understood. We aimed to investigate the relationship between expression of BTG3 and clinicopathological features and prognosis, as well as to explore the effects and the role of a possible BTG3 molecular mechanism on aggressive colorectal cancer behavior.Methods: BTG3 expression was assessed by immunohistochemistry (IHC) on specimens from 140 patients with CRC. The association of BTG3 expression with clinicopathological features was examined. To confirm the biological role of BTG3 in CRC, two CRC cell lines expressing BTG3 were used and BTG3 expression was knocked down by shRNA. CCK-8, cell cycle, apoptosis, migration, and invasion assays were performed. The influence of BTG3 knockdown was further investigated by genomic microarray to uncover the potential molecular mechanisms underlying BTG3-mediated CRC development and progression.Results: BTG3 was downregulated in colorectal cancer tissues and positively correlated with pathological classification (p = 0.037), depth of invasion (p = 0.016), distant metastasis (p = 0.024), TNM stage (p = 0.007), and overall survival (OS) and disease-free survival (DFS). BTG3 knockdown promoted cell proliferation, migration, invasion, relieved G2 arrest, and inhibited apoptosis in HCT116 and LoVo cells. A genomic microarray analysis showed that numerous tumor-associated signaling pathways and oncogenes were altered by BTG3 knockdown. At the mRNA level, nine genes referred to the extracellular-regulated kinase/mitogen-activated protein kinase pathway were differentially expressed. Western blotting revealed that BTG3 knockdown upregulated PAK2, RPS6KA5, YWHAB, and signal transducer and activator of transcription (STAT)3 protein levels, but downregulated RAP1A, DUSP6, and STAT1 protein expression, which was consistent with the genomic microarray data.Conclusions: BTG3 expression might contribute to CRC carcinogenesis. BTG3 knockdown might strengthen the aggressive colorectal cancer behavior. [ABSTRACT FROM AUTHOR]

Background/Aims: MicroRNAs have been validated to play a crucial role in tumorigenesis of non-small cell lung cancer (NSCLC). Although miR-106b-5p has been reported to play a vital role in various malignancies the physiological function of miR-106b-5p in NSCLC still remain unknown. In this study, we investigated the role of miR-106b-5p in NSCLC. Methods: Quantitative real-time polymerase chain reaction was conducted to estimate the expression of miR-106b-5p and BTG3 in both NSCLC tissues and cell lines. The effects of miR-106b-5p on proliferation were determined in vitro using CCK-8 proliferation assays, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, colony formation assays and cell-cycle assays and the in vivo effects were evaluated by a mouse tumorigenicity model. Cell apoptosis and cell cycle was investigated by flow cytometric analysis in vitro. The molecular mechanism underlying the relevance between miR-106b-5p and BTG3 was confirmed by luciferase assay and western blot. Results: In current study, we found a relatively higher miR-106b-5p and lower BTG3 expression in NSCLC specimens and cell lines. BTG3 was verified as a direct target of miR-106b-5p by luciferase assay. In vitro, over-expression of miR-106b-5p promoted proliferation and inhibited apoptosis by down-regulating BTG3 expression. In vivo, miR-106b-5p promoted xenograft tumor formation. Conclusion: Our findings revealed for the first time that miR-106b-5p plays a tumorigenesis role in NSCLC progression by down-regulating BTG3 expression, which may lead to a novel insight to the potential biomarker and novel therapeutic strategies for NSCLC patients. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer (EOC) is the leading cause of cancer-related death among all the gynecological malignancies of the female genital system, and its incidence and mortality rates continue to rise. B-cell translocation gene 3 (BTG3) plays an important role in the occurrence and development of numerous cancers. However, the role of BTG3 in EOC remains poorly understood. In this study, we aimed to investigate the biological role and potential molecular mechanism of BTG3 in EOC. We found that BTG3 protein expression was significantly lower in human EOC cell lines. Next, BTG3 upregulation by transfection with pcDNA3.1-BTG inhibited cell proliferation and invasion but promoted cell apoptosis in 2 human EOC cell lines, SKOV-3 and HO-8910 cells. In addition, BTG3 knockdown by small interfering RNA promoted cell proliferation and invasion, but inhibited cell apoptosis in 2 human EOC cell lines, SKOV-3 and HO-8910 cells. Importantly, several proteins, including phosphorylation serine/threonine kinase (p-AKT), phosphorylated glycogen synthase kinase 3β (p-GSK3β), and β-catenin, were markedly decreased by BTG3 upregulation, whereas increased by BTG3 knockdown. Taken together, the results of our study suggest that BTG3 overexpression could inhibit cell proliferation and invasion and promotes cell apoptosis in EOC cell, possibly by regulating the AKT/GSK3β/β-catenin signaling pathway, providing novel insights into the treatment of EOC through BTG3 overexpression. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) are defined as a class of RNA transcripts longer than 200 nucleotides encoded by mammalian genomes that lack protein-coding potential. LncRNA ASBEL has been identified as an anti-sense transcript of BTG3 (B cell translocation gene 3) gene, which encodes an anti-proliferation protein. Remarkable down-regulation of BTG3 has been reported in triple-negative breast cancer (TNBC). In the present study, a number of single-stranded modified anti-sense DNA oligonucleotides (antago) were designed, synthesized and screened for specific lncRNA ASBEL knockdown. We showed here that anti-ASBEL antago played a significant tumor suppressive role in TNBC by effective down-regulating lncRNA ASBEL, which in turn led to increased BTG3 expression. The obtained data suggest lncRNA ASBEL as a novel therapeutic target in TNBC. [ABSTRACT FROM AUTHOR]

Background: Esophageal squamous carcinoma (ESC) is one of the most fatal malignancies worldwide with increasing occurrences yet poor outcome. MicroRNAs were reported to play roles in ESC.Aims: We aimed to understand how miRNAs affect the radiotherapy resistance of ESC.Methods: MicroRNA assays, real-time PCR, and Western blot were performed for expression analysis of miR-93 and BTG3. Luciferase activity assay was conducted with mutated B-cell translocation gene 3 (BTG3) 3'-UTR sequence in the 3' end of luciferase sequence with miR-93 inhibitor. ESC cells were treated with irradiation (IR) and clonogenic assay was utilized to detect the cell viability. Human ESC xenograft mouse model was established and subjected to target IR treatment followed by tumor size analysis.Results: MiR-93 was decreased and BTG3 was increased in ESC cells, with negative correlation of their expression in ESC tissues. MiR-93 directly targeted BTG3 3'-UTR by luciferase activity assay. Either miR-93 inhibition or BTG3 overexpression decreased radiation resistance. Furthermore, miR-93 inhibition suppressed radiation resistance through BTG3.Conclusions: Direct downregulation of BTG3 by miR-93 is able to render ESC resistant to radiotherapy, and both BTG3 and miR-93 may potentially serve as clinical markers for ESC and contribute to the treatment of ESC. [ABSTRACT FROM AUTHOR]

This study investigated the underlying mechanism of miR-18a-5p regulating the proliferation, invasion, and metastasis of nasopharyngeal carcinoma (NPC) cells in vitro and in vivo to indicate the pathogenesis of NPC. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was utilized to determine miR-18a-5p expression level in NPC tissues and cell lines. Besides, 2,5-diphenyl-2 H-tetrazolium bromide (MTT) and colony formation assays were employed to detect the effect of miR-18a-5p expression level on NPC cell proliferation. Wound healing and Transwell assays were utilized to detect the effect of miR-18a-5p on NPC cell invasion and migration. The expression levels of epithelial-mesenchymal transition (EMT)-related proteins (Vimentin, N-cadherin, and E-cadherin) were identified by Western blot assay. After collecting exosomes from CNE-2 cells, it was found that exosomal miR-18a-5p secreted from NPC cells promoted NPC cell proliferation, migration, invasion, and EMT, whereas inhibition of miR-18a-5p expression level led to the opposite results. The dual-luciferase reporter assay showed that BTG anti-proliferation factor 3 (BTG3) was the target gene of miR-18a-5p, and BTG3 could overturn the effect of miR-18a-5p on NPC cells. Xenograft mouse model of NPC nude mice showed that miR-18a-5p promoted NPC growth and metastasis in vivo. This study revealed that exosomal miR-18a-5p derived from NPC cells promoted angiogenesis via targeting BTG3 and activating the Wnt/β-catenin signaling pathway.

Growing pieces of evidence reported abnormal expression of microRNA in various cancer. Our research aimed to ascertain the miR-142-5p expression and its potential function in the growth and metastasis of human nasopharyngeal carcinoma (NPC). In human NPC tissues and cell lines, miR-142-5p expression was quantified via the real-time qPCR assay. Functionally, the potential effect of miR-142-5p in human CNE-1 and SUNE-1 cells through MTT assay, colony formation assay, Transwell assay, and cell cycle assay. In addition, the potential target gene of miR-142-5p was determined by the dual-luciferase reporter assay. MiR-142-5p expression was remarkably elevated in human NPC tissues, CNE-1 and SUNE-1 cells. MiR-142-5p overexpression obviously enhanced the ability of cell proliferative and colony formation, and prevented G1 phase arrest in CNE-1 and SUNE-1 cells. Further, the migration number of NPC cells was increased compared to NP69 cells. BTG3 was identified as the direct target gene of miR-142-5p. Inhibition of BTG3 expression could reverse the cell proliferation by miR-142-5p-induced. Overall, miR-142-5p could strengthen the NPC cell's proliferation and migration by directly targeting BTG3. Hence, miR-142-5p may provide a new strategy and program for future clinical treatment of NPC.

B cell translocation gene 3 (BTG3) is a tumor suppressor by inhibiting cell proliferation, migration, and regulating cell cycle progression in several tumors. However, its role in esophageal adenocarcinoma (EAC) remains unknown. Here, we detected the expression of BTG3 in EAC tissues and subsequent progression. BTG3 expression was significant decreased in EAC tissues and cell lines detected by real-time RT-PCR and Western blot. Relationships of BTG3 with EAC clinicopathology were analyzed statistically. The decrease expression of BTG3 is associated with lymph node metastases. In vitro assay demonstrated that overexpression of BTG3 significantly suppressed colony formation and proliferation of EAC cells. The suppressed migration and invasion abilities found in BTG3-overexpressing EAC cells. Our findings suggested that BTG3 is suppressor in the progression of EAC. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is one of the most common malignancies in China. B-cell translocation gene 3 (BTG3) has been identified as a tumor suppressor in several tumors, but its role in GC remains unknown. This study aimed to detect the expression of BTG3 and its prognostic value in GC tissues and determine its function in the progression of GC. Methodology: The expression of BTG3 was detected in GC cell lines and tissues by real-time RT-PCR, Western blot or immunohistochemistry. A series of in vitro and in vivo assays were performed to evaluate the effect of BTG3 on proliferation, migration and invasion of GC cells. Results: B-cell translocation gene 3 was obviously down-regulated in GC tissues. Its expression was positively correlated with distant metastasis ( P < 0.05). Patients with lower BTG3 expression had shorter overall survival time ( P = 0.015). BTG3 suppressed the proliferation of GC cells in vitro and in vivo. It also inhibited migration and invasion of GC cells in vitro. Conclusion: Down-regulation of BTG3 is closely associated with proliferation, migration and invasion in GC. It may be a novel prognostic biomarker for GC patients. [ABSTRACT FROM AUTHOR]

Down syndrome (DS), one of the most common birth defects and the most widespread genetic cause of intellectual disabilities, is caused by extra genetic material on chromosome 21 (HSA21). The increased genomic dosage of trisomy 21 is thought to be responsible for the distinct DS phenotypes, including an increased risk of developing some types of childhood leukemia and germ cell tumors. Patients with DS, however, have a strikingly lower incidence of many other solid tumors. We hypothesized that the third copy of genes located in HSA21 may have an important role on the protective effect that DS patients show against most types of solid tumors. Focusing on Copy Number Variation (CNV) array data, we have generated frequencies of deleted regions in HSA21 in four different tumor types from which DS patients have been reported to be protected. We describe three different regions of deletion pointing to a set of candidate genes that could explain the inverse comorbidity phenomenon between DS and solid tumors. In particular we found RCAN1 gene in Wilms tumors and a miRNA cluster containing miR-99A, miR-125B2 and miR-LET7C in lung, breast, and melanoma tumors as the main candidates for explaining the inverse comorbidity observed between solid tumors and DS. [ABSTRACT FROM AUTHOR]

B cell transposition gene 3 (BTG3) is reported to be a tumor suppressor and suppresses proliferation and cell cycle progression. This study aims to analyze the clinicopathological and prognostic significances, and signal pathways of BTG3 mRNA expression in human beings through bioinformatics analysis. We analyzed BTG3 expression using Oncomine, TCGA (the cancer genome atlas), Xiantao, UALCAN (The University of ALabama at Birmingham Cancer data analysis Portal) and Kaplan-Meier plotter databases. Down-regulated BTG3 expression was observed in lung and breast cancers, compared with normal tissues ( p < 0.05), but not for gastric and ovarian cancer ( p < 0.05). The methylation of BTG3 was shown to be adversely correlated with its mRNA expression ( p < 0.05). BTG3 expression was higher in gastric intestinal-type than diffuse-type carcinomas, G 1 than G 3 carcinomas ( p < 0.05), in female than male cancer patients, T 1-2 than T 3-4 , and adenocarcinoma than squamous cell carcinoma of lung cancer ( p < 0.05), in invasive ductal than lobular carcinoma, N 0 than N 1 and N 3 , TNBC (triple-negative breast cancer) than luminal and Her2+, and Her2+ than luminal cancer of breast cancer ( p < 0.05), and G 3 than G 2 ovarian carcinoma ( p < 0.05). BTG3 expression was positively related to the survival rate of gastric and ovarian cancer patients ( p < 0.05), but not for breast cancer ( p < 0.05). KEGG and PPI (protein-protein interaction) analysis showed that the BTG3 was involved in cell cycle and DNA replication, digestion and absorption of fat and protein, spliceosome and ribosome in cancer. BTG3 expression was positively linked to carcinogenesis, histogenesis, and aggressive behaviors, and was employed to evaluate the prognosis of cancers by regulating cell cycle, metabolism, splicing and translation of RNA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zheng, Xue, Zhang, Shi and Zhang.)

B-cell translocation gene 3 (BTG3) is a member of the BTG family which inhibits cell proliferation, metastasis, and angiogenesis, and also regulates cell-cycle progression and differentiation in a variety of cell types. However, there is no study to analyze BTG3 expression in epithelial ovarian carcinoma (EOC). Here, we investigated the expression of BTG3 in EOC carcinogenesis and subsequent progression. BTG3 mRNA expression was detected by real-time RT-PCR in ovarian benign and malignant tumors. The expression of BTG3 protein was examined by immunohistochemistry on tissue microarrays containing ovarian normal tissue, benign and borderline epithelial ovarian tumors, and EOCs. Relationships of BTG3 with both EOC clinicopathology and prognosis were analyzed statistically. The expression of BTG3 protein was also evaluated in ovarian normal tissue, benign tumors, and EOCs by western blot. The BTG3 mRNA expression level was higher in ovarian normal tissue and benign tumors than that in borderline, primary, and metastatic carcinoma ( p < 0.05), and was negatively correlated with dedifferentiation and FIGO staging of EOC ( p < 0.05). Using western blot, BTG3 protein was found lower in EOCs compared to the normal and benign tumors ( p < 0.05), and poorly differentiated EOCs showed lower BTG3 expression than well-differentiated and moderately differentiated EOCs ( p < 0.05). Immunohistochemically, BTG3 protein expression was statistically lower in EOCs than normal tissue and benign tumors ( p < 0.05). EOC patients with low BTG3 protein expression showed a higher incidence of metastasis ( p = 0.020), poor differentiation ( p = 0.030), and shorter disease-free time and overall survival time ( p < 0.05). By using Cox's proportional hazard model, BTG3 protein expression and FIGO staging were independent prognostic factors for both disease-free time and overall survival time of EOCs ( p < 0.05). It was suggested that down-regulated BTG3 expression might play roles in the pathogenesis and aggressiveness of EOC. BTG3 protein expression may be considered as a good marker to indicate the favorable prognosis of EOCs. [ABSTRACT FROM AUTHOR]

Abstract: Vascular smooth muscle cell (VSMC) proliferation plays a key role in neointimal hyperplasia and restenosis. Here we report the role of the microRNA miR-142-5p and its downstream target genes on the proliferation of cultured VSMCs. miR-142-5p promoted VSMC proliferation by down-regulating B cell translocation gene 3 (BTG3). We found that BTG3 inhibited the expression of cell cycle regulatory genes and cell growth. As shown by luciferase reporter assay, miR-142-5p bound directly to the 3′-untranslated region of BTG3. Overexpression of miR-142-5p induced expression of cell cycle regulatory genes. Thus, BTG3, a novel, direct target of miR-142-5p, negatively regulates VSMC proliferation. [Copyright &y& Elsevier]

Highlights: [•] BTG3 expression is frequently suppressed in NSCLC. [•] Two BTG3 isoforms present in lung cancer. [•] BTG3 inhibits lung cancer growth. [•] Restoration of BTG3 inhibits autophagy in lung cancer cells. [Copyright &y& Elsevier]

The article presents a study on the capability of genistein to induce B-cell translocation gene 3 (BGT3) gene expression and influence enzymatic activities. It says that ginestein and 5-aza-2'-deoxycytidine (5Aza-C) were used to treat prostate cancer and normal cell lines. It shows that genistein increase the level of BTG3 and inhibited DNA methyltransferase (DNMT). Also, it adds that genistein is an advantageous therapeutic agent for prostate cancer due to its nontoxic and dietary isoflavone.

Abstract: BTG2 and BTG3 are two members of the B-cell translocation gene family with anti-proliferative properties. BTG1 gene in this gene family has been reported to play a key role in muscle growth. In this study, we identified and characterized the porcine BTG2 and BTG3 genes, mapped the two genes to porcine chromosomes, and analyzed their expression differences in the longissimus dorci muscle of 33 dpc (day postconception), 65 dpc and 90 dpc in the lean Landrace and fatty Chinese Tongcheng pig breeds. Expression changes in differentiated C2C12 cells were also investigated with myogenin as internal control. The results showed that the porcine BTG2 and BTG3 genes were mapped on SSC9q21-25 and SSC13q47, respectively. BTG2 gene expressed at high levels in skeletal muscle and heart in both Tongcheng and Landrace pigs whereas BTG3 gene expressed at lower levels in skeletal muscle and heart than in other tissues. Furthermore, BTG3 expressed at higher levels in skeletal muscle of Tonghceng compared with Landrace pig. The expression of BTG2 and BTG3 was significantly different in skeletal muscle among different developmental stages and between the two breeds. Expression analysis in murine myoblast cells showed that both genes were induced in differentiated C2C12 cells, suggesting a role of them in myogenic differentiation. Our study indicated that BTG2 and BTG3, especially BTG3 gene, may be important genes for skeletal muscle growth. [Copyright &y& Elsevier]

Objective: To study the association of BTG3 , CASP9 and LRP4 single-nucleotide polymorphisms with susceptibility to papillary thyroid carcinoma (PTC). Methods: The BTG3 rs9977638, CASP9 rs884363 and LRP4 rs898604 genotypes of 175 PTC patients and 175 controls were analyzed. Results: Rs9977638 TC genotype and CC genotype, rs884363 CC genotype and rs898604 GG genotype were related to a lower PTC susceptibility risk (p < 0.01). The risk of PTC susceptibility was higher when carrying BTG3 rs9977638 CC, CASP9 rs884363 AC and LRP4 rs898604 AG at the same time (p < 0.01). Conclusion: Combined BTG3 , CASP9 and LRP4 genotype analysis has a certain application value in the diagnosis of PTC.

Dysregulated microRNAs (miRNAs) are involved in carcinoma progression, metastasis, and poor prognosis. We demonstrated that in nasopharyngeal carcinoma (NPC), transactivated MIR106A-5p promotes a malignant phenotype by functioning as a macroautophagy/autophagy suppressor by targeting BTG3 (BTG anti-proliferation factor 3) and activating autophagy-regulating MAPK signaling. MIR106A-5p expression was markedly increased in NPC cases based on quantitative real-time PCR, miRNA microarray, and TCGA database analysis findings. Moreover, MIR106A-5p was correlated with advanced stage, recurrence, and poor clinical outcomes in NPC patients. In addition to three-dimensional cell culture assays, zebrafish and BALB/c mouse tumor models revealed that overexpressed MIR106A-5p targeted BTG3 and accelerated the NPC malignant phenotype by inhibiting autophagy. BTG3 promoted autophagy, and its expression was correlated with poor prognosis in NPC. Attenuation of autophagy, mediated by the MIR106A-5p -BTG3 axis, occurred because of MAPK pathway activation. MIR106A-5p overexpression in NPC was due to increased transactivation by EGR1 and SOX9. Our findings may lead to novel insights into the pathogenesis of NPC. Abbreviations: ACTB: actin beta; ATG: autophagy-related; ATG5: autophagy related 5; BLI: bioluminescence; BTG3: BTG anti-proliferation factor 3; CASP3: caspase 3; ChIP: chromatin immunoprecipitation; CQ: chloroquine; Ct: threshold cycle; DAPI: 4',6-diamidino-2-phenylindole; DiL: 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate; EBSS: Earle's balanced salt solution; EGR1: early growth response 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GEO: Gene Expression Omnibus; GFP: green fluorescent protein; IF: immunofluorescence; IHC: immunohistochemistry; ISH: in situ hybridization; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MIR106A-5p: microRNA 106a-5p; miRNAs: microRNAs; MKI67: marker of proliferation ki-67; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; NPC: nasopharyngeal carcinoma; qRT-PCR: quantitative real-time PCR; siRNA: small interfering RNA; SOX9: SRY-box transcription factor 9; SQSTM1: sequestosome 1; TCGA: The Cancer Genome Atlas; WB: western blot.

• MiR-519c-3p expression is upregulated in HCC. • The high level of miR-519c-3p correlates with poor prognosis of HCC. • MiR-519c-3p facilitates the growth and metastasis of HCC cells. • BTG3 is a direct target of miR-519c-3p in HCC. • BTG3 mediates the tumor promoting effect of miR-519c-3p in HCC. Tumor recurrence and metastasis after surgical resection are the major causes for the cancer-related death of hepatocellular carcinoma (HCC). Thus, better understanding the mechanisms involved in tumor progression will benefit to improve HCC treatment. Accumulating evidence demonstrates that microRNAs (miRNAs) play critical roles in the development and progression of HCC. However, the function of miR-519c-3p in HCC and its related mechanism remain unexplored. Here, we reported that miR-519c-3p was strongly overexpressed in HCC tissues, which was significantly correlated with poor prognosis and clinicopathological features including tumor size ≥5 cm, vascular invasion and advanced tumor-node-metastasis (TNM) stages (III + IV). Furthermore, the elevated levels of miR-519c-3p were observed in HCC cell lines. Subsequently, gain- or loss-of-function assays demonstrated that miR-519c-3p promoted HCC cell proliferation, migration as well as invasion in vitro , and facilitated the growth and metastasis of HCC cells in vivo. Mechanistically, B-cell translocation gene 3 (BTG3) was identified as a direct downstream target of miR-519c-3p. The level of BTG3 mRNA was downregulated in HCC and negatively correlated with miR-519c-3p expression. Western blotting confirmed that BTG3 was negatively regulated by miR-519c-3p in HCC cells. Luciferase reporter assays illustrated the direct interaction between miR-519c-3p and the 3′UTR of BTG3 mRNA. Recuse experiments demonstrated that BTG3 mediated the promoting effects of miR-519c-3p on the proliferation and motility of HCC cells. Collectively, our results suggest that miR-519c-3p functions as a tumor promotor in regulating the growth and metastasis of HCC by targeting BTG3, and potentially serves as a novel therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

5-Fluorouracil (5-FU)-based chemotherapy has always been the first-line treatment of colorectal cancer (CRC). However, the occurrence of clinical 5-FU resistance is a major reason for CRC therapy failure. This study intended to explore the possible role of long non-coding RNA HOTAIRM1 (HOTAIRM1) in the pathogenesis of 5-FU resistant CRC and its underlying mechanism. Our data showed that HOTAIRM1 was downregulated in CRC tissues and cell lines (HCT116 and SW480), and even lower in 5-FU resistant CRC tissues and cell lines (HCT116/5-FU and SW480/5-FU). In vitro, effects of HOTAIRM1 dysregulation in 5-FU resistant CRC cells were investigated and its overexpression could reduce cell viability, invasion, migration, and multi-drug resistance as evidenced by MTT assay, Transwell assay, epithelial-mesenchymal transition (EMT), and western blot analyzing expression of drug-resistant genes MRP1 and MDR1, respectively. Mechanically, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) identified that HOTAIRM1 and B-cell translocation gene 3 (BTG3) were target genes of miR-17-5p. Moreover, miR-17-5p was upregulated and BTG3 was downregulated in HCT116/5-FU and SW480/5-FU cells. Silencing of miR-17-5p showed suppressive role on cell viability, invasion, migration, and multi-drug resistance in HCT116/5-FU and SW480/5-FU cells, which could be abolished by HOTAIRM1 knockdown. Similarly, ectopic expression of miR-17-5p reversed BTG3-mediated inhibition on cell viability, invasion, migration, and multi-drug resistance. In vivo, the tumorigenesis of HCT116/5-FU cells when highly expressed HOTAIRM1 by lentivirus infection was inhibited through downregulating miR-17-5p and upregulating BTG3. In conclusion, HOTAIRM1 might act as a tumor-suppressor in 5-FU resistant CRC cells in vitro and in vivo through downregulating miR-17-5p/BTG3 pathway and inhibiting multi-drug resistance. [ABSTRACT FROM AUTHOR]

Purpose: Some microRNA (miRNA) levels have been found to be dysregulated in cancer patients, suggesting the potential usefulness of miRNAs in cancer therapies. The purpose of this study was to investigate the expression of miR-142-5p in human renal cell carcinoma (RCC) and its potential role in tumor growth and metastasis., Methods: The expression level of miR-142-5p in human RCC tissue and cell lines was determined by quantitative reverse transcription polymerase chain reaction analysis. MTT, colony formation, Transwell, and cell cycle assays were performed to explore the potential functions of miR-142-5p in human RCC cells. The potential target gene of miR-142-5p was identified and confirmed via luciferase reporter assays., Results: miR-142-5p expression was elevated in RCC tissues and cell lines. Overexpression of miR-142-5p significantly promoted cell proliferation and colony formation and could prevent G1 phase arrest among RCC 786-O cells. Meanwhile, the migration potential of 786-O cells was greater than that of control cells. BTG3 was identified as a direct target of miR-142-5p, and re-expression of BTG3 reversed the miR-142-5p-induced cell proliferation., Conclusion: miR-142-5p promoted the proliferation and migration of RCC cells by targeting BTG3. With this potential onco-miRNA role in the progression of RCC, miR-142-5p may be a therapeutic target for the treatment of RCC., Competing Interests: None.

Background: Epithelial-mesenchymal transition (EMT) and dysregulated microRNAs (miRNAs) have important roles in driving chemoresistance. We previously reported that iASPP is a key EMT inducer and could increase cisplatin resistance in cervical cancer (CC) cells. Herein, we investigate the downstream mechanisms through which iASPP contributes to EMT and cisplatin resistance in CC., Methods: By using a lentiviral system, we investigated the effects of iASPP knockdown on CC cell growth and chemosensitivity of CC cells to cisplatin in vivo. We examined if miR-20a, which was up-regulated following iASPP overexpression, would influence metastatic phenotypes and cisplatin resistance in CC cells, and explored the possible molecular mechanisms involved., Results: Knockdown of iASPP suppressed CC cell proliferation and sensitized CC cells to cisplatin in vivo. iASPP promotes miR-20a expression in a p53-dependent manner. Upregulation of miR-20a induced EMT and the recovery of CC cell invasion and cisplatin chemoresistance that was repressed by iASPP knockdown. We identified FBXL5 and BTG3 as two direct miR-20a targets. Silencing of FBXL5 and BTG3 restored cell invasion and cisplatin chemoresistance, which was suppressed by iASPP or miR-20a knockdown. Reduced FBXL5 and BTG3 expression was found in CC samples and associated with poor prognosis in CC patients., Conclusions: iASPP promotes EMT and confers cisplatin resistance in CC via miR-20a-FBXL5/BTG3 signaling.

Here, we found that down-regulated expression of BTG3 might be positively correlated with colorectal carcinogenesis and its overexpression suppressed proliferation, glycolysis, mitochondrial respiration, cell cycle progression, migration, and invasion, and induced apoptosis, senescence and differentiation in SW480 and SW620 cells. After treated with cisplatin, MG132, paclitaxel and SAHA, BTG3 transfectants exhibited lower viability and higher apoptosis than the control in both time- and dose-dependent manners. BTG3 overexpression up- regulated the protein expression of Cyclin E, p16, p27, NF-κB, p38α/β, XIAP, Bcl-2, ATG14 and p53, but down-regulated the mRNA expression of MRP1, BCRP, and mTOR in SW480 and SW620 cells. BTG3 overexpression inhibited tumor growth of SW620 cells by suppressing proliferation and inducing apoptosis. It was suggested that down-regulated BTG3 expression might be considered as a marker for colorectal carcinogenesis. BTG3 overexpression might reverse the aggressive phenotypes and be employed as a potential target for gene therapy of colorectal cancer.