Overexpressing lipid raft protein STOML2 modulates the tumor microenvironment via NF-κB signaling in colorectal cancer.

Colorectal cancer (CRC) is characterized by a complex tumor inflammatory microenvironment, while angiogenesis and immunosuppression frequently occur concomitantly. However, the exact mechanism that controls angiogenesis and immunosuppression in CRC microenvironment remains unclear. Herein, we found that expression levels of lipid raft protein STOML2 were increased in CRC and were associated with advanced disease stage and poor survival outcomes. Intriguingly, we revealed that STOML2 is essential for CRC tumor inflammatory microenvironment, which induces angiogenesis and facilitates tumor immune escape simultaneously both in vitro and in vivo. Moreover, tumors with STOML2 overexpression showed effective response to anti-angiogenesis treatment and immunotherapy in vivo. Mechanistically, STOML2 regulates CRC proliferation, angiogenesis, and immune escape through activated NF-κB signaling pathway via binding to TRADD protein, resulting in upregulation of CCND1, VEGF, and PD-L1. Furthermore, treatment with NF-κB inhibitor dramatically reversed the ability of proliferation and angiogenesis. Clinically, we also observed a strong positive correlation between STOML2 expression and Ki67, CD31, VEGFC and PD-1 of CD8+T cell expression. Taken together, our results provided novel insights into the role of STOML2 in CRC inflammatory microenvironment, which may present a therapeutic opportunity for CRC.

An endoplasmic reticulum stress-related signature could robustly predict prognosis and closely associate with response to immunotherapy in pancreatic ductal adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors. Endoplasmic reticulum stress (ERS) plays an essential role in PDAC progression. Here, we aim to identify the ERS-related genes in PDAC and build reliable risk models for diagnosis, prognosis and immunotherapy response of PDAC patients as well as investigate the potential mechanism. METHODS: We obtained PDAC cohorts with transcriptional profiles and clinical data from the ArrayExpress, The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Univariate Cox regression, LASSO regression and multivariate Cox regression analyses were used to construct an ERS-related prognostic signature. The CIBERSORT and ssGSEA algorithms were applied to explore the correlation between the prognostic signature and immune cell infiltration and immune-related pathways. The GDSC database and TIDE algorithm were used to predict responses to chemotherapy and immunotherapy, identifying potential drugs for treating patients with PDAC. RESULTS: We established and validated an ERS-related prognostic signature comprising eight genes (HMOX1, TGFB1, JSRP1, GAPDH, CAV1, CHRNE, CD74 and ERN2). Patients with higher risk scores displayed worse outcomes than those with lower risk scores. PDAC patients in low-risk groups might benefit from immunotherapy. Dasatinib and lapatinib might have potential therapeutic implications in high-risk PDAC patients. CONCLUSION: We established and validated an ERS-related prognostic signature comprising eight genes to predict the overall survival outcome of PDAC patients, which closely correlating with the response to immunotherapy and sensitivity to anti-tumor drugs, as well as could be beneficial for formulating clinical strategies and administering individualized treatments.

RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition.

The RNF43_p.G659fs mutation occurs frequently in colorectal cancer, but its function remains poorly understood and there are no specific therapies directed against this alteration. In this study, we find that RNF43_p.G659fs promotes cell growth independent of Wnt signaling. We perform a drug repurposing library screen and discover that cells with RNF43_p.G659 mutations are selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yield promising antitumor activity in RNF43659mut isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_p.G659fs mutations. We find that RNF43659mut binds p85 leading to increased PI3K signaling through p85 ubiquitination and degradation. Additionally, RNA-sequencing of RNF43659mut isogenic cells reveals decreased interferon response gene expression, that is reversed by PI3K/mTOR inhibition, suggesting that RNF43659mut may alter tumor immunity. Our findings suggest a therapeutic application for PI3K/mTOR inhibitors in treating RNF43_p.G659fs mutant cancers.

Identification of an unfolded protein response-related signature for predicting the prognosis of pancreatic ductal adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy. An effective prognosis prediction model is urgently needed for treatment optimization. Methods: The differentially expressed unfolded protein response (UPR)‒related genes between pancreatic tumor and normal tissue were analyzed using the TCGA-PDAC dataset, and these genes that overlapped with UPR‒related prognostic genes from the E-MTAB-6134 dataset were further analyzed. Univariate, LASSO and multivariate Cox regression analyses were applied to establish a prognostic gene signature, which was evaluated by Kaplan‒Meier curve and receiver operating characteristic (ROC) analyses. E‒MTAB‒6134 was set as the training dataset, while TCGA-PDAC, GSE21501 and ICGC-PACA-AU were used for external validation. Subsequently, a nomogram integrating risk scores and clinical parameters was established, and gene set enrichment analysis (GSEA), tumor immunity analysis and drug sensitivity analysis were conducted. Results: A UPR-related signature comprising twelve genes was constructed and divided PDAC patients into high- and low-risk groups based on the median risk score. The UPR-related signature accurately predicted the prognosis and acted as an independent prognostic factor of PDAC patients, and the AUCs of the UPR-related signature in predicting PDAC prognosis at 1, 2 and 3 years were all more than 0.7 in the training and validation datasets. The UPR-related signature showed excellent performance in outcome prediction even in different clinicopathological subgroups, including the female (p<0.0001), male (p<0.0001), grade 1/2 (p<0.0001), grade 3 (p=0.028), N0 (p=0.043), N1 (p<0.001), and R0 (p<0.0001) groups. Furthermore, multiple immune-related pathways were enriched in the low-risk group, and risk scores in the low-risk group were also associated with significantly higher levels of tumor-infiltrating lymphocytes (TILs). In addition, DepMap drug sensitivity analysis and our validation experiment showed that PDAC cell lines with high UPR-related risk scores or UPR activation are more sensitive to floxuridine, which is used as an antineoplastic agent. Conclusion: Herein, we identified a novel UPR-related prognostic signature that showed high value in predicting survival in patients with PDAC. Targeting these UPR-related genes might be an alternative for PDAC therapy. Further experimental studies are required to reveal how these genes mediate ER stress and PDAC progression.

eVIP2: Expression-based variant impact phenotyping to predict the function of gene variants.

While advancements in genome sequencing have identified millions of somatic mutations in cancer, their functional impact is poorly understood. We previously developed the expression-based variant impact phenotyping (eVIP) method to use gene expression data to characterize the function of gene variants. The eVIP method uses a decision tree-based algorithm to predict the functional impact of somatic variants by comparing gene expression signatures induced by introduction of wild-type (WT) versus mutant cDNAs in cell lines. The method distinguishes between variants that are gain-of-function, loss-of-function, change-of-function, or neutral. We present eVIP2, software that allows for pathway analysis (eVIP Pathways) and usage with RNA-seq data. To demonstrate the eVIP2 software and approach, we characterized two recurrent frameshift variants in RNF43, a negative regulator of Wnt signaling, frequently mutated in colorectal, gastric, and endometrial cancer. RNF43 WT, RNF43 R117fs, RNF43 G659fs, or GFP control cDNA were overexpressed in HEK293T cells. Analysis with eVIP2 predicted that the frameshift at position 117 was a loss-of-function mutation, as expected. The second frameshift at position 659 has been previously described as a passenger mutation that maintains the RNF43 WT function as a negative regulator of Wnt. Surprisingly, eVIP2 predicted G659fs to be a change-of-function mutation. Additional eVIP Pathways analysis of RNF43 G659fs predicted 10 pathways to be significantly altered, including TNF-α via NFκB signaling, KRAS signaling, and hypoxia, highlighting the benefit of a more comprehensive approach when determining the impact of gene variant function. To validate these predictions, we performed reporter assays and found that each pathway activated by expression of RNF43 G659fs, but not expression of RNF43 WT, was identified as impacted by eVIP2, supporting that RNF43 G659fs is a change-of-function mutation and its effect on the identified pathways. Pathway activation was further validated by Western blot analysis. Lastly, we show primary colon adenocarcinoma patient samples with R117fs and G659fs variants have transcriptional profiles similar to BRAF missense mutations with activated RAS/MAPK signaling, consistent with KRAS signaling pathways being GOF in both variants. The eVIP2 method is an important step towards overcoming the current challenge of variant interpretation in the implementation of precision medicine. eVIP2 is available at https://github.com/BrooksLabUCSC/eVIP2.

Actin-like protein 6A/MYC/CDK2 axis confers high proliferative activity in triple-negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high proliferative activity. TNBC tumors exhibit elevated MYC expression and altered expression of MYC regulatory genes, which are associated with tumor progression and poor prognosis; however, the underlying mechanisms by which MYC retains its high expression and mediates TNBC tumorigenesis require further exploration. METHODS: ACTL6A regulation of MYC and its target gene, CDK2, was defined using Co-IP, mass spectrometry and ChIP assays. To study the role of ACTL6A in TNBC, we performed soft-agar, colony formation, flow cytometry and tumor formation in nude mice. CDK2 inhibitor and paclitaxel were used in testing combination therapy in vitro and in vivo. RESULTS: ACTL6A bound MYC to suppress glycogen synthase kinase 3 beta (GSK3ß)-induced phosphorylation on MYC T58, which inhibited ubiquitination of MYC and stabilized it. Moreover, ACTL6A promoted the recruitment of MYC and histone acetyltransferase KAT5 on CDK2 promoters, leading to hyperactivation of CDK2 transcription. ACTL6A overexpression promoted, while silencing ACTL6A suppressed cell proliferation and tumor growth in TNBC cells in vitro and in vivo, which was dependent on MYC signaling. Furthermore, co-therapy with paclitaxel and CDK2 inhibitor showed synergistic effects in tumor suppression. Notably, ACTL6A/MYC/CDK2 axis was specifically up-regulated in TNBC and high expression of ACTL6A was correlated to shorter survival in patients with TNBC. CONCLUSIONS: These findings reveal a novel mechanism by which ACTL6A prolongs the retention of MYC in TNBC and suggest that pharmacological targeting ACTL6A/MYC/CDK2 axis might have therapeutic potential in patients with TNBC.

MYEOV functions as an amplified competing endogenous RNA in promoting metastasis by activating TGF-ß pathway in NSCLC.

Non-small cell lung cancer (NSCLC) remains a major cause of death worldwide. As metastatic disease is primarily responsible for the poor clinical outcome of NSCLC, it is important to understand the process, and its underlying molecular mechanism as well, via which NSCLC cells disseminate. In this study, we identified a new competing endogenous RNA (ceRNA), namely, the MYEOV transcript, and found that it is upregulated in NSCLC and associated with a poor prognosis of the disease. We further uncovered that the MYEOV ceRNA plays a critical role in the invasion and metastasis of NSCLC cells. Intriguingly, the MYEOV ceRNA exerted its pro-metastatic function independent of its protein-coding capacity, but in a miR-30c-2-3p binding-dependent manner. Further experiments demonstrated that the MYEOV ceRNA sequestered miR-30c-2-3p from binding its targets TGFBR2 and USP15 mRNAs, which in turn leading to constitutive activation of TGF-ß signaling and tumor progression in NSCLC. By identifying a new layer of regulatory modality for TGF-ß signaling, our findings extend the current understanding on the molecular mechanism mediating NSCLC progression and highlight a potential role of MYEOV transcript to serve as the therapeutic target.

CK1α suppresses lung tumour growth by stabilizing PTEN and inducing autophagy.

The contribution of autophagy to cancer development remains controversial, largely owing to the fact that autophagy can be tumour suppressive or oncogenic in different biological contexts. Here, we show that in non-small-cell lung cancer (NSCLC), casein kinase 1 alpha 1 (CK1α) suppresses tumour growth by functioning as an autophagy inducer to activate an autophagy-regulating, tumour-suppressive PTEN/AKT/FOXO3a/Atg7 axis. Specifically, CK1α bound the C-terminal tail of PTEN and enhanced both PTEN stability and activity by competitively antagonizing NEDD4-1-induced PTEN polyubiquitination and abrogating PTEN phosphorylation, thereby inhibiting AKT activity and activating FOXO3a-induced transcription of Atg7. Notably, blocking CK1α-induced Atg7-dependent autophagy cooperates with oncogenic HRasV12 to initiate tumorigenesis of lung epithelial cells. An association of a CK1α-modulated autophagic program with the anti-neoplastic activities of the CK1α/PTEN/FOXO3a/Atg7 axis was demonstrated in xenografted tumour models and human NSCLC specimens. This provides insights into the biological and potentially clinical significance of autophagy in NSCLC.

Publisher Correction: Simultaneous overactivation of Wnt/ß-catenin and TGFß signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC.

This corrects the article DOI: 10.1038/ncomms15870.

miR­873 inhibits colorectal cancer cell proliferation by targeting TRAF5 and TAB1.

MicroRNA-873 (miR­873) has been reported to be dysregulated in a variety of malignancies, however, the biological function and underlying molecular mechanism of miR­873 in colorectal cancer (CRC) remain unclear. In the present study we found that the expression levels of miR­873 were markedly decreased in CRC cell lines and tissues from patients. Statistical analysis revealed that miR­873 expression was inversely correlated with the disease stage of CRC. Kaplan­Meier survival analysis revealed that patients with CRC with lower miR­873 expression had shorter overall survival rates. Additionally, downregulation of miR­873 enhanced the proliferation of CRC cells, while upregulation of miR­873 reduced this proliferation. Furthermore, we found that tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) and TGF­ß activated kinase 1 (MAP3K7) binding protein 1 (TAB1) were direct targets of miR­873 in CRC cells. A luciferase assay revealed that ectopic expression of miR­873 significantly reduced nuclear factor κB (NF­κB) luciferase activity, while ectopic expression of miR­873 inhibitor enhanced luciferase activity, suggesting that downregulation of miR­873 can activate NF­κB signaling. Therefore, our findings established a tumor-suppressive role for miR­873 in the inhibition of CRC progression, which may be employed as a novel prognostic marker and as an effective therapeutic target for CRC.

Simultaneous overactivation of Wnt/ß-catenin and TGFß signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC.

Cancer chemoresistance and metastasis are tightly associated features. However, whether they share common molecular mechanisms and thus can be targeted with one common strategy remain unclear in non-small cell lung cancer (NSCLC). Here, we report that high levels of microRNA-128-3p (miR-128-3p) is key to concomitant development of chemoresistance and metastasis in residual NSCLC cells having survived repeated chemotherapy and correlates with chemoresistance, aggressiveness and poor prognosis in NSCLC patients. Mechanistically, miR-128-3p induces mesenchymal and stemness-like properties through downregulating multiple inhibitors of Wnt/ß-catenin and TGF-ß pathways, leading to their overactivation. Importantly, antagonism of miR-128-3p potently reverses metastasis and chemoresistance of highly malignant NSCLC cells, which could be completely reversed by restoring Wnt/ß-catenin and TGF-ß activities. Notably, correlations among miR-128-3p levels, activated ß-catenin and TGF-ß signalling, and pro-epithelial-to-mesenchymal transition/pro-metastatic protein levels are validated in NSCLC patient specimens. These findings suggest that miR-128-3p might be a potential target against both metastasis and chemoresistance in NSCLC.

URGCP promotes non-small cell lung cancer invasiveness by activating the NF-κB-MMP-9 pathway.

Invasion and metastasis are main traits of tumor progression and responsible for the poor prognosis of advanced non-small cell lung cancer (NSCLC). The molecular mechanisms underlying the malignant behaviors of NSCLC remain incompletely understood. The present study demonstrate that up-regulator of cell proliferation (URGCP), a recently identified tumor-promoting gene found in several tumor types, is markedly overexpressed in human NSCLC cell lines and clinical NSCLC samples. URGCP upregulation correlates significantly with the progression and poor prognosis of this disease. In vitro and in vivo studies demonstrate that increasing URGCP expression accelerates invasion, migration, and distant metastasis of NSCLC cells whereas downregulating URGCP suppresses these malignant traits. Notably, silencing URGCP expression almost completely abrogates the metastatic ability of NSCLC cells. At the molecular level, URGCP markedly promotes MMP-9 expression by activating NF-κB signaling. Additionally, URGCP and MMP-9 expression are positively correlated in various cohorts of human NSCLC specimens, and NF-κB-activated MMP-9 expression contributes to URGCP-induced invasiveness of NSCLC cell lines. Collectively, these findings indicate that URGCP plays an important role in promoting NSCLC cell invasion and metastasis by enhancing NF-κB-activated MMP-9 expression and may serve as a potential therapeutic target and prognostic marker.

Aberrantly expressed miR-582-3p maintains lung cancer stem cell-like traits by activating Wnt/ß-catenin signalling.

Cancer stem cells (CSCs) are involved in tumorigenesis, tumour recurrence and therapy resistance and Wnt signalling is essential for the development of the biological traits of CSCs. In non-small cell lung carcinoma (NSCLC), unlike in colon cancer, mutations in ß-catenin and APC genes are uncommon; thus, the mechanism underlying the constitutive activation of Wnt signalling in NSCLC remains unclear. Here we report that miR-582-3p expression correlates with the overall- and recurrence-free-survival of NSCLC patients, and miR-582-3p has an activating effect on Wnt/ß-catenin signalling. miR-582-3p overexpression simultaneously targets multiple negative regulators of the Wnt/ß-catenin pathway, namely, AXIN2, DKK3 and SFRP1. Consequently, miR-582-3p promotes CSC traits of NSCLC cells in vitro and tumorigenesis and tumour recurrence in vivo. Antagonizing miR-582-3p potently inhibits tumour initiation and progression in xenografted animal models. These findings suggest that miR-582-3p mediates the constitutive activation of Wnt/ß-catenin signalling, likely serving as a potential therapeutic target for NSCLC.

MicroRNA-542-3p Suppresses Tumor Cell Invasion via Targeting AKT Pathway in Human Astrocytoma.

The molecular mechanism underlying constitutive activation of AKT signaling, which plays essential roles in astrocytoma progression, is not fully characterized. Increasing numbers of studies have reported that microRNAs are involved in the malignant behavior of astrocytoma cells via directly targeting multiple oncogenes or tumor suppressors. Here, we found that microRNA (miR)-542-3p expression was decreased in glioblastoma cell lines and astrocytoma tissues, and reduced levels of miR-542-3p expression correlated with high histopathological grades and poor prognosis of astrocytoma patients. Exogenous miR-542-3p suppressed glioblastoma cell invasion through not only targeting AKT1 itself but also directly down-regulating its two important upstream regulators, namely, integrin-linked kinase and PIK3R1. Notably, overexpressing miR-542-3p decreased AKT1 phosphorylation and directly and indirectly repressed nuclear translocation and transactivation activity of ß-catenin to exert its anti-invasive effect. Furthermore, the miR-542-3p expression level negatively correlated with AKT activity as well as levels of integrin-linked kinase and PIK3R1 in human astrocytoma specimens. These findings suggest that miR-542-3p acts as a negative regulator in astrocytoma progression and that miR-542-3p down-regulation contributes to aberrant activation of AKT signaling, leaving open the possibility that miR-542-3p may be a potential therapeutic target for high grade astrocytoma.

miR-205 targets PTEN and PHLPP2 to augment AKT signaling and drive malignant phenotypes in non-small cell lung cancer.

AKT signaling is constitutively activated in various cancers, due in large part to loss-of-function in the PTEN and PHLPP phosphatases that act as tumor suppressor genes. However, AKT signaling is activated widely in non-small cell lung cancers (NSCLC) where genetic alterations in PTEN or PHLPP genes are rare, suggesting an undefined mechanism(s) for their suppression. In this study, we report upregulation of the oncomir microRNA (miR)-205 in multiple subtypes of NSCLC, which directly represses PTEN and PHLPP2 expression and activates both the AKT/FOXO3a and AKT/mTOR signaling pathways. miR-205 overexpression in NSCLC cells accelerated tumor cell proliferation and promoted blood vessel formation in vitro and in vivo. Conversely, RNA interference-mediated silencing of endogenous miR-205 abrogated these effects. The malignant properties induced by miR-205 in NSCLC cells were reversed by AKT inhibitors, FOXO3a overexpression, rapamycin treatment, or restoring PHLPP2 or PTEN expression. Mechanistic investigations revealed that miR-205 overexpression was a result of NF-κB-mediated transactivation of the miR-205 gene. Taken together, our results define a major epigenetic mechanism for suppression of PTEN and PHLPP2 in NSCLC, identifying a pivotal role for miR-205 in development and progression of this widespread disease.

Overexpression of MACC1 and Its significance in human Breast Cancer Progression.

BACKGROUND: Metastasis-associated in colon cancer-1 (MACC1) was first identified as a transcriptional activator for proto-oncogene c-MET expression, and its overexpression is frequently associated with metastatic progression for multiply tumor types. In the present study, we analyzed for the first time the expression of MACC1 in breast cancer and its correlation with clinicopathologic features, including metastasis and patient survival. RESULTS: MACC1 protein expression was analyzed in two cohorts of clinicopathologically characterized breast cancer using immunohistochemistry. Statistical analysis showed a significant correlation of MACC1 expression with the primary tumor, lymph node metastasis, distant metastasis classifications as well as the clinical staging in breast cancer patients. Moreover, overexpression of MACC1 was associated with both a reduced recurrence-free survival (RFS) and poorer patients' overall survival (OS). Multivariate analysis with a Cox proportional-hazards model suggested that MACC1 expression was an independent prognostic indicator for RFS and OS. Stratification of breast cancer patients according to the estrogen receptor (ER) status revealed that MACC1 was prognostic for both ER-negative and ER-positive patients. CONCLUSIONS: MACC1 may represent a potentially useful biomarker for the prognosis of breast cancer patients and might be involved in progression of breast cancer.

MicroRNA-374a activates Wnt/ß-catenin signaling to promote breast cancer metastasis.

Tumor metastasis involves a series of biological steps during which the tumor cells acquire the ability to invade surrounding tissues and survive outside the original tumor site. During the early stages, the cancer cells undergo an epithelial-mesenchymal transition (EMT). Wnt/ß-catenin signaling is known to drive EMT and metastasis. Here we report that Wnt/ß-catenin signaling is hyperactivated in metastatic breast cancer cells that express microRNA 374a (miR-374a). In breast cancer cell lines, ectopic overexpression of miR-374a promoted EMT and metastasis both in vitro and in vivo. Furthermore, miR-374a directly targeted and suppressed multiple negative regulators of the Wnt/ß-catenin signaling cascade, including WIF1, PTEN, and WNT5A. Notably, miR-374a was markedly upregulated in primary tumor samples from patients with distant metastases and was associated with poor metastasis-free survival. These results demonstrate that miR-374a maintains constitutively activated Wnt/ß-catenin signaling and may represent a therapeutic target for early metastatic breast cancer.

miR-186 downregulation correlates with poor survival in lung adenocarcinoma, where it interferes with cell-cycle regulation.

Deeper mechanistic understanding of lung adenocarcinoma (non-small cell lung carcinoma, or NSCLC), a leading cause of cancer-related deaths overall, may lead to more effective therapeutic strategies. In analyzing NSCLC clinical specimens and cell lines, we discovered a uniform decrease in miR-186 (MIR186) expression in comparison with normal lung tissue or epithelial cell lines. miR-186 expression correlated with patient survival, with median overall survival time of 63.0 or 21.5 months in cases exhibiting high or low levels of miR-186, respectively. Enforced overexpression of miR-186 in NSCLC cells inhibited proliferation by inducing G(1)-S checkpoint arrest. Conversely, RNA interference-mediated silencing miR-186 expression promoted cell-cycle progression and accelerated the proliferation of NSCLC cells. Cyclin D1 (CCND1), cyclin-dependent kinase (CDK)2, and CDK6 were each directly targeted for inhibition by miR-186 and restoring their expression reversed miR-186-mediated inhibition of cell-cycle progression. The inverse relationship between expression of miR-186 and its targets was confirmed in NSCLC tumor xenografts and clinical specimens. Taken together, our findings established a tumor-suppressive role for miR-186 in the progression of NSCLC.

MiR-136 promotes apoptosis of glioma cells by targeting AEG-1 and Bcl-2.

MicroRNAs have the capacity to coordinately repress multiple target genes and interfere with biological functions of the cell, such as proliferation and apoptosis. Here we report that miR-136 is downregulated in human glioma, and that the miRNA promotes apoptosis of glioma cells induced by chemotherapy. Two anti-apoptotic genes, AEG-1 and Bcl-2, are identified as targets of miR-136, and restoration of AEG-1 or Bcl-2 expression suppresses miR-136-enhanced apoptosis. Therefore, miR-136 might play a tumor-suppressive role in human glioma and thereby might represent a potential therapeutic strategy.