YES Proto-oncogene Research Articles

ACSL3 regulates breast cancer progression via lipid metabolism reprogramming and the YES1/YAP axis.

Mitochondrial fatty acid oxidation is a metabolic pathway whose dysregulation is recognized as a critical factor in various cancers, because it sustains cancer cell survival, proliferation, and metastasis. The acyl-CoA synthetase long-chain (ACSL) family is known to activate long-chain fatty acids, yet the specific role of ACSL3 in breast cancer has not been determined. We assessed the prognostic value of ACSL3 in breast cancer by using data from tumor samples. Gain-of-function and loss-of-function assays were also conducted to determine the roles and downstream regulatory mechanisms of ACSL3 in vitro and in vivo. ACSL3 expression was notably downregulated in breast cancer tissues compared with normal tissues, and this phenotype correlated with improved survival outcomes. Functional experiments revealed that ACSL3 knockdown in breast cancer cells promoted cell proliferation, migration, and epithelial-mesenchymal transition. Mechanistically, ACSL3 was found to inhibit β-oxidation and the formation of associated byproducts, thereby suppressing malignant behavior in breast cancer. Importantly, ACSL3 was found to interact with YES proto-oncogene 1, a member of the Src family of tyrosine kinases, and to suppress its activation through phosphorylation at Tyr419. The decrease in activated YES1 consequently inhibited YAP1 nuclear colocalization and transcriptional complex formation, and the expression of its downstream genes in breast cancer cell nuclei. ACSL3 suppresses breast cancer progression by impeding lipid metabolism reprogramming, and inhibiting malignant behaviors through phospho-YES1 mediated inhibition of YAP1 and its downstream pathways. These findings suggest that ACSL3 may serve as a potential biomarker and target for comprehensive therapeutic strategies for breast cancer.

LncRNA12097.1 contributes to endometrial cell growth by enhancing YES1 activating β-catenin via sponging miR-145-5p

Despite previous investigations elucidating the regulatory mechanisms of long non-coding RNAs (lncRNAs) in endometrial function and reproductive disorders, the precise pathways through which lncRNAs impact endometrial functions and fertility remain unclear. In this study, we performed an expression profile analysis of lncRNAs in the endometrial tissue of Hu sheep with different prolificacy, identifying 13,707 lncRNAs. We discovered a bidirectional lncRNA, designated lncRNA12097.1, exhibiting significant up-regulation exclusively in the endometrium of Hu sheep with high fecundity. Functional analyses revealed lncRNA12097.1 significantly enhanced proliferation and cell cycle progression in both endometrial epithelial cell (EEC) and stromal cells (ESC), while inhibiting apoptosis in these cell types. Mechanistically, we demonstrated a directly interaction between lncRNA12097.1 and miR-145-5p, with YES proto-oncogene 1 (YES1) being identified as a validated target of miR-145-5p. Interference with lncRNA12097.1 resulted in suppressed cell growth through down-regulation of YES1 expression, which could be rescued by miR-145-5p. Furthermore, lncRNA12097.1 functions as a competitive endogenous RNA (ceRNA) for miR-145-5p in ESCs, sequestering miR-145-5p and preventing its binding to the 3′UTR of YES1 mRNA. This interaction led to increased expression of YES1 and subsequent activation of downstream β-catenin signaling, thereby promoting ESC growth in Hu sheep. These findings provide novel molecular insights into the mechanisms underlying prolificacy in sheep.

Role of YES1 signaling in tumor therapy resistance.

YES proto-oncogene 1 (YES1) is anSRC family kinase (SFK) that plays a key role in cancer cell proliferation, adhesion, invasion, survival, and angiogenesis during tumorigenesis and tumor development. Reports suggest that YES1 amplification is associated with resistance to chemotherapeutic drugs and tyrosine kinase inhibitors (TKIs) in human malignancies. However, the mechanisms of drug resistance have not been fully elucidated. In this article, we review the literature on YES1 and discuss the implications of YES1 signaling for targeted therapy and chemotherapy resistance in malignancies. Moreover, recent advances in targeted therapy for YES1-amplified malignancies are summarized. Finally, we conclude that targeting YES1 may reverse drug resistance and serve as a valuable tumor treatment strategy.

Effect of Nanoparticles of DOX and miR-125b on DNA Damage Repair in Glioma U251 Cells and Underlying Mechanisms.

Glioma is the most common primary craniocerebral malignant tumor, arising from the canceration of glial cells in the brain and spinal cord. The quality of life and prognosis of patients with this disease are still poor. Doxorubicin (DOX) is one of the most traditional and economical chemotherapeutic drugs for the treatment of glioma, but its toxic effect on normal cells and the resistance of tumor cells to DOX make the application of DOX in the treatment of glioma gradually less effective. To solve this problem, we co-encapsulated DOX and endogenous tumor suppressor miR-125b into nanoparticles (NPs) by nanoprecipitation methods, and passively targeted them into glioma cells. In vitro experiments show that miR-125b and DOX can be effectively encapsulated into nanoparticles with different ratios, and by targeting YES proto-oncogene 1 (YES1), they can affect the adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)/p53 pathway and induce brain glioma cell apoptosis. They can also affect the DNA damage repair process and inhibit cell proliferation. The obtained data suggest that co-delivery of DOX and miR-125b could achieve synergistic effects on tumor suppression. Nanosystem-based co-delivery of tumor suppressive miRNAs and chemotherapeutic agents may be a promising combined therapeutic strategy for enhanced anti-tumor therapy.

Circ_0081143 Contributes to Gastric Cancer Malignant Development and Doxorubicin Resistance by Elevating the Expression of YES1 by Targeting mziR-129-2-3p.

The increased mortality of gastric cancer (GC) is mainly attributed to the development of chemoresistance. Circular RNAs, as the novel type of biomarkers in GC, have attracted wide attention. The purpose of this study was to investigate the functional role of circ_0081143 in GC with doxorubicin (DR) resistance and its potential action mechanism. The expression of circ_0081143, miR-129-2-3p and YES proto-oncogene 1 (YES1) in GC tissues and cells was measured by quantitative real-time polymerase chain reaction. The half maximal inhibitory concentration value was calculated based on the MTT cell viability assay. Cell proliferation and apoptosis were monitored by MTT and flow cytometry assays. Transwell assays were employed to check cell migration and invasion. The protein levels of YES1 and apoptosis-related proteins were detected by western blotting. The interaction between miR-129-2-3p and circ_0081143 or YES1 was verified by dual-luciferase reporter and pull-down assays. A tumorigenicity assay was conducted to verify the role of circ_0081143 in vivo. Circ_0081143 was highly expressed in DR-resistant GC tumor tissues and cells. Depletion of circ_0081143 reduced DR resistance and inhibited DR-resistant GC cell proliferation, migration and invasion. Circ_0081143 targeted miR-129-2-3p and inhibited the role of miR-129-2-3p. In addition, YES1 was a target of miR-129-2-3p, and its function was suppressed by miR-129-2-3p. Importantly, circ_0081143 positively modulated the expression of YES1 through mediating miR-129-2-3p. Circ_0081143 knockdown weakened the DR-resistant GC tumor growth in vivo. Circ_0081143 knockdown weakened DR resistance and blocked the development of DR-resistant GC by regulating the miR-129-2-3p/YES1 axis. Our data suggest that circ_0081143 is a promising target for the treatment of GC with DR resistance.

MiR-133a targets YES1 to reduce cisplatin resistance in ovarian cancer by regulating cell autophagy

BackgroundAccumulating evidence has revealed that aberrant microRNA (miRNA) expression can affect the development of chemotherapy drug resistance by modulating the expression of relevant target proteins. Emerging evidence has demonstrated that miR-133a participates in the tumorigenesis of various cancers. However, whether miR-133a is associated with cisplatin resistance in ovarian cancer remains unclear.ObjectiveTo investigate the role of miR-133a in the development of cisplatin resistance in ovarian cancer.MethodsMiR-133a expression in cisplatin-resistant ovarian cancer cell lines was assessed by reverse-transcription quantitative PCR (RT–qPCR). A cell counting kit-8 (CCK-8) assay was used to evaluate the viability of tumour cells treated with cisplatin in the presence or absence of miR-133a. A luciferase reporter assay was used to analyse the binding of miR-133a with the 3′ untranslated region (3′UTR) of YES proto-oncogene 1 (YES1). The YES1 expression level was analysed using a dataset from the International Cancer Genome Consortium (ICGC) and assessed by RT–qPCR and western blotting in vitro. The roles and mechanisms of YES1 in cell functions were further probed via gain- and loss-of-function analysis.ResultsThe expression of miR-133a was significantly decreased in cisplatin-resistant ovarian cancer cell lines (A2780-DDP and SKOV3-DDP), and the overexpression of the miR-133a mimic reduced cisplatin resistance in A2780-DDP and SKOV3-DDP cells. Treatment with the miR-133a inhibitor increased cisplatin sensitivity in normal A2780 and SKOV3 cells. MiR-133a binds the 3’UTR of YES1 and downregulates its expression. Bioinformatics analysis revealed that YES1 expression was upregulated in recurrent cisplatin-resistant ovarian cancer tissue, and in vitro experiments also verified its upregulation in cisplatin-resistant cell lines. Furthermore, we discovered that miR-133a downregulated the expression of YES1 and thus inhibited cell autophagy to reduce cisplatin resistance. Yes1 knockdown significantly suppressed the cisplatin resistance of ovarian cancer cells by inhibiting autophagy in vitro. Xenograft tumour implantation further demonstrated that Yes1 overexpression promoted ovarian tumour development and cisplatin resistance.ConclusionsOur results suggest that the miR-133a/YES1 axis plays a critical role in cisplatin resistance in human ovarian cancer by regulating cell autophagy, which might serve as a promising therapeutic target for ovarian cancer chemotherapy treatment in the future.

RBM15 promotes hepatocellular carcinoma progression by regulating N6-methyladenosine modification of YES1 mRNA in an IGF2BP1-dependent manner

The function of the N6-methyladenosine (m6A) methyltransferase RNA-binding motif protein 15 (RBM15) in hepatocellular carcinoma (HCC) has not been thoroughly investigated. Here we determined the clinical value, biological functions, and potential mechanisms of RBM15 in HCC. Expression of RBM15 was identified using tissue microarrays and online databases. A risk-prediction model based on RBM15 was developed and validated. We determined the biological role of RBM15 on HCC cells in vitro and in vivo. RNA sequencing was used to screen candidate targets of RBM15. Subsequently, the m6A dot blot assay, methylated RNA immunoprecipitation qPCR, dual-luciferase reporter assays, RNA decay assay, and RNA immunoprecipitation qPCR were employed to explore the mechanisms of RBM15. Our study showed that RBM15 was highly expressed in HCC, and overexpression of RBM15 indicated a worse outcome. A new nomogram combining RBM15 with age and TNM stage was developed and validated to predict the outcome of HCC patients; our nomogram increased the prediction accuracy of the TNM system. Functionally, RBM15 facilitates the proliferation and invasiveness of HCC. RBM15-mediated m6A modification contributed to a post-transcriptional activation of YES proto-oncogene 1 (YES1) in an insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)-dependent manner. In addition, YES1 was confirmed as an oncogene in HCC cells by activating the mitogen-activated protein kinase (MAPK) pathway. In conclusion, RBM15-mediated m6A modification might facilitate the progression of HCC via the IGF2BP1–YES1–MAPK axis. RBM15 may be a promising biomarker in the outcome prediction of HCC.

EphA2\u2013YES1\u2013ANXA2 pathway promotes gastric cancer progression and metastasis

Erythropoietin-producing hepatocellular receptor A2 (EphA2) is a key member of the receptor tyrosine kinase (RTK) family, while YES Proto-Oncogene 1 (YES1) is a non-receptor tyrosine kinase (nRTK) and annexin A2 (ANXA2) belongs to the calcium-dependent phospholipid-binding protein family annexins. Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, leading to ANXA2 activation and increased ANXA2 nuclear distribution in gastric cancer (GC) cells. Overexpression (OE) of YES1 increases, while knockdown (KD) of YES1 or ANXA2 decreases GC cell invasion and migration in vitro and tumor growth in mouse models. Reexpression of wildtype (WT) rather than mutant ANXA2 (Tyr24F) in ANXA2 knockdown (ANXA2-KD) GC cells restores YES1-induced cell invasion and migration, while neither WT nor mutant ANXA2 (Tyr24F) can restore cell invasion and migration in YES1-KD GC cells. In addition, the activation of EphA2–YES1–ANXA2 pathway is correlated with poor prognosis. Thus, our results establish EphA2–YES1–ANXA2 axis as a novel pathway that drives GC invasion and metastasis, targeting this pathway would be an efficient way for the treatment of GC.

Matrine Regulates Proliferation, Apoptosis, Cell Cycle, Migration, and Invasion of Non-Small Cell Lung Cancer Cells Through the circFUT8/miR-944/YES1 Axis.

BackgroundNon-small cell lung carcinoma (NSCLC) is the major histological subtype of cancer cases. In the present study, we investigated the association between Matrine, an active component of Chinese medicine, and circFUT8 in NSCLC cells.MethodsThe proliferation ability of NSCLC cells was assessed by MTT and colony-forming assays. Flow cytometry assay was performed to show the apoptosis and cell cycle distribution in NSCLC cells. The protein expression levels of Bcl-2, Cleaved Caspase-3 (C-Caspase3), and YES proto-oncogene 1 (YES1) were measured by Western blot assay. Migration and invasion of NSCLC cells were determined by transwell assay. The expression levels of circFUT8, miR-944 and YES1 were quantified by real-time quantitative polymerase chain reaction (RT-qPCR) assay. The interaction relationship between miR-944 and circFUT8 or YES1 was confirmed by dual-luciferase reporter assay. The anti-tumor role of Matrine in vivo was explored by a xenograft experiment.ResultsMatrine functioned as a carcinoma inhibitor by repressing proliferation, cell cycle process, migration, and invasion while inducing apoptosis in NSCLC cells. Importantly, overexpression of circFUT8 counteracted Matrine-induced effects on NSCLC cells. MiR-944, interacted with YES1, was a target of circFUT8. Under Matrine condition, overexpression of circFUT8 increased proliferation, migration, and invasion while inhibited apoptosis, which was abolished by the upregulation of miR-944. Whereas the silencing of YES1 counteracted miR-944 inhibitor-induced effects on NSCLC cells. Eventually, we also confirmed that Matrine impeded NSCLC tumor growth in vivo.ConclusionMatrine regulated proliferation, apoptosis, cell cycle, migration, and invasion of NSCLC cells through the circFUT8/miR-944/YES1 axis, which provided novel information for Matrine in NSCLC.

Circ-ZNF124 downregulation inhibits non-small cell lung cancer progression partly by inactivating the Wnt/β-catenin signaling pathway via mediating the miR-498/YES1 axis.

Non-small cell lung cancer (NSCLC) is a major type of lung cancer, leading to a high fatality rate. The role of circular RNAs (circRNAs) in cancer has been increasingly emphasized and studied. However, the function of circ-ZNF124 in NSCLC is largely unclear, and associated regulatory mechanism is not studied. Here, we examined the expression pattern of circ-ZNF124 using quantitative real-time PCR. For functional analysis, cell proliferation, cell apoptosis/cycle and cell invasion were investigated using MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] assay, flow cytometry assay and transwell assay, respectively. As results, we found that the expression of circ-ZNF124 was elevated in NSCLC tissues and cells. Functionally, circ-ZNF124 downregulation inhibited NSCLC cell proliferation and invasion but induced apoptosis and cycle arrest in vitro, and blocked tumor growth in vivo by animal experiments. Mechanistically, we identified that miR-498 was a target of circ-ZNF124, and miR-498 directly bound to YES proto-oncogene 1 (YES1). Besides, rescue experiments discovered that the cellular effects caused by circ-ZNF124 downregulation could be reversed by miR-498 inhibition or YES1 overexpression. Moreover, we discovered that circ-ZNF124 downregulation inactivated the expression of β-catenin and c-Myc by mediating the miR-498/YES axis. In conclusion, these findings supported that circ-ZNF124 regulated the expression of YES1 by acting as a sponge of miR-498, thus restraining NSCLC development by inactivating the Wnt/β-catenin signaling pathway, which provided a novel strategy to treat NSCLC.

Circ_0057553/miR-515-5p Regulates Prostate Cancer Cell Proliferation, Apoptosis, Migration, Invasion and Aerobic Glycolysis by Targeting YES1.

BackgroundProstate cancer (PCa) is one of the most common malignant cancer in males worldwide. Circular RNAs (CircRNAs) are novel type of non-coding RNAs. Recently, circRNAs have been reported participating in various cancers, including prostate cancer. However, the function and mechanism of circ_0057553 remain to be elucidated.Methods and MaterialsThe RNA expression levels of circ_0057553, miR-515-5p, YES proto-oncogene 1 (YES1) and glycolytic genes mRNA were detected by qRT-PCR in PCa tissues or cells. Western blotting was performed to analyze YES1 protein level. Cell viability, migration and invasion and cell apoptosis were assessed by cell counting kit-8 (CCK-8) assay, transwell assay and flow cytometry. In addition, the effects of cell glycolysis were evaluated by measuring lactate production, glucose consumption and adenosine triphosphate (ATP) level. Moreover, dual-luciferase reporter assay was used to detect the target sites of circ_0057553 and miR-515-5p, miR-515-5p and YES1. RNA immunoprecipitation (RIP) was conducted to evaluate the target relationship between circ_0057553 and miR-515-5p. Xenograft mouse model was conducted to measure tumor formation in vivo.ResultsCirc_0057553 was significantly up-regulated in PCa tissues and cells. Knockdown of circ_0057553 inhibited cell viability, migration, invasion and glycolysis and facilitated apoptosis in PCa cells. Furthermore, circ_0057553 bound to miR-515-5p and miR-515-5p directly targeted YES1. Interestingly, miR-515-5p inhibitor partially rescued the function of circ_0057553 knockdown, while YES1 restored the effects of miR-515-5p overexpression. Circ_0057553 down-regulation remarkably decreased tumor volume and weight in vivo.ConclusionCirc_0057553 affected PCa cell viability, migration, invasion, apoptosis and glycolysis through miR-515-5p/YES1 axis.

Promoter Hypomethylation and Increased Expression of the Long Non-coding RNA LINC00152 Support Colorectal Carcinogenesis

Up-regulation of the long non-coding RNA LINC00152 can contribute to cancer development, proliferation and invasion, including colorectal cancer, however, its mechanism of action in colorectal carcinogenesis and progression is only insufficiently understood. In this work we correlated LINC00152 expression with promoter DNA methylation changes in colorectal tissues along the normal-adenoma-carcinoma sequence and studied the effects of LINC00152 silencing on the cell cycle regulation and on the whole transcriptome in colon carcinoma cells using cell and molecular biology techniques. LINC00152 was significantly up-regulated in adenoma and colorectal cancer (p < 0.001) compared to normal samples, which was confirmed by real-time PCR and in situ hybridization. LINC00152 promoter hypomethylation detected in colorectal cancer (p < 0.01) was strongly correlated with increased LINC00152 expression (r=-0.90). Silencing of LINC00152 significantly suppressed cell growth, induced apoptosis and decreased cyclin D1 expression (p < 0.05). Whole transcriptome analysis of LINC00152-silenced cells revealed significant down-regulation of oncogenic and metastasis promoting genes (e.g. YES proto-oncogene 1, PORCN porcupine O-acyltransferase), and up-regulation of tumour suppressor genes (e.g. DKK1 dickkopf WNT signalling pathway inhibitor 1, PERP p53 apoptosis effector) (adjusted p < 0.05). Pathway analysis confirmed the LINC00152-related activation of oncogenic molecular pathways including those driven by PI3K/Akt, Ras, WNT, TP53, Notch and ErbB. Our results suggest that promoter hypomethylation related overexpression of LINC00152 can contribute to the pathogenesis of colorectal cancer by facilitating cell progression through the up-regulation of several oncogenic and metastasis promoting pathway elements.

Long non-coding TUG1 accelerates prostate cancer progression through regulating miR-128-3p/YES1 axis.

Dysregulation of long non-coding RNAs (lncRNAs) is being found to have relevance to human cancers, including prostate cancer (PCa). Taurine-upregulated gene 1 (TUG1) has been demonstrated to have a potential oncogenic role in PCa. Then the aim of this study was to investigate the molecular mechanisms of TUG1 on PCa progression. The expression levels of TUG1, YES proto-oncogene 1 (YES1) mRNA and miR-128-3p were assessed using quantitative real-time polymerase chain reaction. Cell proliferation ability, apoptosis, and migration and invasion capacities were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, flow cytometry and transwell assay, respectively. Western blot analysis was employed to evaluate the indicated proteins levels. The interaction between miR-128-3p and TUG1 or YES1 was determined using the Dual-Luciferase reporter assay. In vivo assay was used to observe the effect of TUG1 on tumor growth in vivo. Our data indicated that TUG1 was upregulated in PCa tissues and cells and predicted poor prognosis. TUG1 knockdown weakened PCa cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and accelerated cell apoptosis in vitro. Mechanistically, TUG1 directly interacted with miR-128-3p and miR-128-3p mediated the regulatory effects of TUG1 depletion on PCa cell progression. YES1 was a direct target of miR-128-3p and TUG1 modulated YES1 expression by sponging miR-128-3p. Moreover, TUG1 silencing repressed PCa cell progression in vitro through YES1. Additionally, TUG1 silencing mitigated tumor growth in vivo. Our study suggested that TUG1 silencing retarded PCa cell progression in vitro and tumor growth in vivo through miR-128-3p/YES1 axis, showing that targeting TUG1 might be a novel therapeutic strategy for PCa management.

MiR-133 Targets YES1 and Inhibits the Growth of Triple-Negative Breast Cancer Cells

Triple-negative breast cancer shows worse outcome compared with other subtypes of breast cancer. The discovery of dysregulated microRNAs and their roles in the progression of triple-negative breast cancer provide novel strategies for the treatment of patients with triple-negative breast cancer. In this study, we identified the significant reduction of miR-133 in triple-negative breast cancer tissues and cell lines. Ectopic overexpression of miR-133 suppressed the proliferation, colony formation, and upregulated the apoptosis of triple-negative breast cancer cells. Mechanism study revealed that the YES Proto-Oncogene 1 was a target of miR-133. miR-133 bound the 3′-untranslated region of YES Proto-Oncogene 1 and decreased the level of YES Proto-Oncogene 1 in triple-negative breast cancer cells. Consistent with miR-133 downregulation, YES1 was significantly increased in triple-negative breast cancer, which was inversely correlated with the level of miR-133. Restoration of YES Proto-Oncogene 1 attenuated the inhibitory effects of miR-133 on the proliferation and colony formation of triple-negative breast cancer cells. Consistent with the decreased expression of YES Proto-Oncogene 1, overexpression of miR-133 suppressed the phosphorylation of YAP1 in triple-negative breast cancer cells. Our results provided novel evidence for the role of miR-133/YES1 axis in the development of triple-negative breast cancer, which indicated miR-133 might be a potential therapeutic strategy for triple-negative breast cancer.

YES1 Is a Targetable Oncogene in Cancers Harboring YES1 Gene Amplification.

Targeting genetic alterations of oncogenes by molecular-targeted agents (MTA) is an effective approach for treating cancer. However, there are still no clinical MTA options for many cancers, including esophageal cancer. We used a short hairpin RNA library to screen for a new oncogene in the esophageal cancer cell line KYSE70 and identified YES proto-oncogene 1 (YES1) as having a significant impact on tumor growth. An analysis of clinical samples showed that YES1 gene amplification existed not only in esophageal cancer but also in lung, head and neck, bladder, and other cancers, indicating that YES1 would be an attractive target for a cancer drug. Because there is no effective YES1 inhibitor so far, we generated a YES1 kinase inhibitor, CH6953755. YES1 kinase inhibition by CH6953755 led to antitumor activity against YES1-amplified cancers in vitro and in vivo. Yes-associated protein 1 (YAP1) played a role downstream of YES1 and contributed to the growth of YES1-amplified cancers. YES1 regulated YAP1 transcription activity by controlling its nuclear translocation and serine phosphorylation. These findings indicate that the regulation of YAP1 by YES1 plays an important role in YES1-amplified cancers and that CH6953755 has therapeutic potential in such cancers. SIGNIFICANCE: These findings identify the SRC family kinase YES1 as a targetable oncogene in esophageal cancer and describe a new inhibitor for YES1 that has potential for clinical utility.See related commentary by Rai, p. 5702.

MicroRNA-133a inhibits the proliferation of non-small cell lung cancer by targeting YES1.

Previous studies have reported that microRNA-133a (miR-133a) is involved in the pathogenesis of human cancers. This study investigated the effect of miR-133a on cell proliferation in non-small cell lung cancer (NSCLC). The expression of miR-133a and YES proto-oncogene 1 (YES1) was detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay. The CCK-8 assay was used to measure cell proliferation. The relationship between miR-133a and YES1 was confirmed by dual luciferase assay. Downregulation of miR-133a was identified in NSCLC and correlated with poor prognosis in NSCLC patients. Moreover, the overexpression of miR-133a inhibited proliferation of NSCLC cells. YES1 was also confirmed as a direct target of miR-133a. Downregulation of YES1 was found to inhibit cell proliferation in NSCLC. By contrast, the upregulation of YES1 abolished the inhibitory effect of miR-133a on cell proliferation in NSCLC. miR-133a inhibited cell proliferation in NSCLC by targeting YES1, indicating that miR-133a can be used as an indicator of prognosis in NSCLC patients.

MicroRNA‐140 inhibit prostate cancer cell invasion and migration by targeting YES proto‐oncogene 1

Prostate cancer (PCa), which is an aggressive malignancy of the male genitourinary system. In the present study, the effects of microRNA-140 (miR-140) on PCa were determined. We transfected miR-140 mimics or negative control into PCa cells, and we used MTT, wound healing, and Transwell assays for determining the capacities of miR-140 in cell proliferation, migration, and invasion, respectively. We also confirmed the relationship between miR-140 and YES proto-oncogene 1 (YES1) using Luciferase reporter assay. The results showed that miR-140 was downregulated in PCa cells and tissues, and overexpression of miR-140 could significantly suppress their capacities of proliferation, migration, and invasion. Moreover, YES1 was shown to be a direct target of miR-140. Moreover, miR-140 expression is negatively correlated with YES1 levels. miR-140 exhibits significant tumor-suppressive effects in PCa by inhibiting YES1. The study indicated that miR-140 and YES1 could be the potential targets for PCa therapy.

Effect of miR-140-5p on the regulation of proliferation and apoptosis in NSCLC and its underlying mechanism.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer accounting for ~80% of lung cancer cases. According to novel research, numerous microRNAs (miRs) have been suggested to function as important regulators of cancer. In addition, the expression of miR-140-5p is decreased in patients with NSCLC. Therefore, it is important to further elucidate the role of miR-140-5p in NSCLC. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used in order to investigate the expression of miR-140-5p in NSCLC tissues and matched normal tissues and to determine miR-140-5p levels following transfection with mimics into A549 lung cancer cells. Targetscan software was used to predict the oncogene target of miR-140-5p. This analysis revealed that YES proto-oncogene 1 (YES1) includes a target site for miR-140-5p binding. The results revealed that YES1 is a potential target gene of miR-140-5p, and this was further confirmed by the results of luciferase reporter assays, which demonstrated that miR-140-5p directly targeted the predicted binding site in the 3'-untranslated region of YES1. Cell Counting Kit-8 (CCK-8) and flow cytometry assays were performed to determine the levels of cell viability and apoptosis. Western blot assays was performed to investigate the expression levels of YES1 and proteins associated with apoptosis in A549 cells following transfection. The results revealed that miR-140-5p expression was significantly downregulated in NSCLC tissues compared with matched normal tissues. The expression of miR-140-5p was significantly increased following transfection with miR-140-5p mimics. The results of CCK-8 and flow cytometry assays indicated that miR-140-5p inhibited proliferation and induced apoptosis of tumor cells. Western blot analysis and RT-qPCR revealed that YES1 and B-cell lymphoma 2 (Bcl-2) mRNA and protein expression levels were markedly decreased in A549 cells, while Bcl-2 associated X (Bax) and caspase-3 expression levels increased significantly following transfection with miR-140-5p mimics compared with the negative control group. In conclusion, miR-140-5p may induce apoptosis in A549 cells by targeting YES1 and regulating the expression of apoptosis-associated proteins Bcl-2, Bax and caspase-3.

Circ_Lrp6, a Circular RNA Enriched in Vascular Smooth Muscle Cells, Acts as a Sponge Regulating miRNA-145 Function.

microRNAs (miRNAs) modulate gene expression by repressing translation of targeted genes. Previous work has established a role for miRNAs in regulating vascular smooth muscle cell (VSMC) activity. Whether circular RNAs are involved in the modulation of miRNA activity in VSMCs is unknown. We aimed to identify circular RNAs interacting with miRNAs enriched in VSMCs and modulating the cells' activity. RNA sequencing and bioinformatics identified several circular RNAs enriched in VSMCs; however, only one, possessing multiple putative binding sites for miR-145, was highly conserved between mouse and man. This circular RNA gemmed from alternative splicing of Lrp6 (lipoprotein receptor 6), a gene highly expressed in vessels and implicated in vascular pathologies and was thus named circ_Lrp6. Its role as a miR-145 sponge was confirmed by determining reciprocal interaction through RNA immunoprecipitation, stimulated emission depletion microscopy, and competitive luciferase assays; functional inhibition of miR-145 was assessed by measuring expression of the target genes ITGβ8 (integrin-β8), FASCIN (fascin actin-bundling protein 1), KLF4 (Kruppel-like factor 4), Yes1 (YES proto-oncogene 1), and Lox (lysyl oxidase). The interaction was preferentially localized to P-bodies, sites of mRNA degradation. Using loss- and gain-of-function approaches, we found that circ_Lrp6 hindered miR-145-mediated regulation of VSMC migration, proliferation, and differentiation. Differential expression of miR-145 and circ_Lrp6 in murine and human vascular diseases suggests that the ratio of circ_Lrp6 bound to miR-145 versus unbound could play a role in vascular pathogenesis. Viral delivery of circ_Lrp6 shRNA prevented intimal hyperplasia in mouse carotids. circ_Lrp6 is an intracellular modulator and a natural sponge for miR-145, counterbalancing the functions of the miRNA in VSMCs.

Re-exploring the core genes and modules in the human frontal cortex during chronological aging: insights from network-based analysis of transcriptomic studies.

Frontal cortical dysfunction is a fundamental pathology contributing to age-associated behavioral and cognitive deficits that predispose older adults to neurodegenerative diseases. It is established that aging increases the risk of frontal cortical dysfunction; however, the underlying molecular mechanism remains elusive. Here, we used an integrative meta-analysis to combine five frontal cortex microarray studies with a combined sample population of 161 younger and 155 older individuals. A network-based analysis was used to describe an outline of human frontal cortical aging to identify core genes whose expression changes with age and to reveal the interrelationships among these genes. We found that histone deacetylase 1 (HDAC1) and YES proto-oncogene 1 (YES1) are the two most upregulated genes, while cell division cycle 42 (CDC42) is the central regulatory gene decreased in the aged human frontal cortex. Quantitative PCR assays revealed corresponding changes in frontal cortical Hdac1, Yes1 and Cdc42 mRNA levels in an established aging mouse model. Moreover, analysis of the GSE48350 dataset confirmed similar changes in HDAC1, CDC42 and YES1 expression in Alzheimer's disease, thereby providing a molecular connection between aging and Alzheimer's disease (AD). This framework of network-based analysis could provide novel strategies for detecting and monitoring aging in the brain.