Gene Summary

Gene:BCL2L11; BCL2 like 11
Aliases: BAM, BIM, BOD
Summary:The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The protein encoded by this gene contains a Bcl-2 homology domain 3 (BH3). It has been shown to interact with other members of the BCL-2 protein family and to act as an apoptotic activator. The expression of this gene can be induced by nerve growth factor (NGF), as well as by the forkhead transcription factor FKHR-L1, which suggests a role of this gene in neuronal and lymphocyte apoptosis. Transgenic studies of the mouse counterpart suggested that this gene functions as an essential initiator of apoptosis in thymocyte-negative selection. Several alternatively spliced transcript variants of this gene have been identified. [provided by RefSeq, Jun 2013]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:bcl-2-like protein 11
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: BCL2L11 (cancer-related)

de Almeida BP, Apolónio JD, Binnie A, Castelo-Branco P
Roadmap of DNA methylation in breast cancer identifies novel prognostic biomarkers.
BMC Cancer. 2019; 19(1):219 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast cancer is a highly heterogeneous disease resulting in diverse clinical behaviours and therapeutic responses. DNA methylation is a major epigenetic alteration that is commonly perturbed in cancers. The aim of this study is to characterize the relationship between DNA methylation and aberrant gene expression in breast cancer.
METHODS: We analysed DNA methylation and gene expression profiles from breast cancer tissue and matched normal tissue in The Cancer Genome Atlas (TCGA). Genome-wide differential methylation analysis and methylation-gene expression correlation was performed. Gene expression changes were subsequently validated in the METABRIC dataset. The Oncoscore tool was used to identify genes that had previously been associated with cancer in the literature. A subset of genes that had not previously been studied in cancer was chosen for further analysis.
RESULTS: We identified 368 CpGs that were differentially methylated between tumor and normal breast tissue (∆β > 0.4). Hypermethylated CpGs were overrepresented in tumor tissue and were found predominantly (56%) in upstream promoter regions. Conversely, hypomethylated CpG sites were found primarily in the gene body (66%). Expression analysis revealed that 209 of the differentially-methylated CpGs were located in 169 genes that were differently expressed between normal and breast tumor tissue. Methylation-expression correlations were predominantly negative (70%) for promoter CpG sites and positive (74%) for gene body CpG sites. Among these differentially-methylated and differentially-expressed genes, we identified 7 that had not previously been studied in any form of cancer. Three of these, TDRD10, PRAC2 and TMEM132C, contained CpG sites that showed diagnostic and prognostic value in breast cancer, particularly in estrogen-receptor (ER)-positive samples. A pan-cancer analysis confirmed differential expression of these genes together with diagnostic and prognostic value of their respective CpG sites in multiple cancer types.
CONCLUSION: We have identified 368 DNA methylation changes that characterize breast cancer tumor tissue, of which 209 are associated with genes that are differentially-expressed in the same samples. Novel DNA methylation markers were identified, of which cg12374721 (PRAC2), cg18081940 (TDRD10) and cg04475027 (TMEM132C) show promise as diagnostic and prognostic markers in breast cancer as well as other cancer types.

Su W, Zhang X, Cai X, et al.
BIM deletion polymorphism predicts poor response to EGFR-TKIs in nonsmall cell lung cancer: An updated meta-analysis.
Medicine (Baltimore). 2019; 98(10):e14568 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A germline deletion in BIM (B cell lymphoma-2-like 11) gene has been shown to impair the apoptotic response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in vitro but its impact on response to EGFR-TKIs in patients of nonsmall cell lung cancer (NSCLC) remains controversial.
METHODS: Eligible literature were searched and screened. Objective response rate (ORR) and disease control rate (DCR) were extracted and aggregated with odds ratio (OR). Hazard ratio (HR) and 95% confidence interval (CI) for progression-free survival (PFS) and overall survival (OS) were extracted and aggregated based on random-effect model.
RESULTS: Fourteen studies including 2694 NSCLC patients were eligible. Individuals harboring BIM deletion polymorphism had inferior ORR (OR = 0.49, 95% CI: 0.34-0.70, P < .001), inferior DCR (OR = 0.50, 95% CI: 0.30-0.84, P = .009). Patients with BIM deletion had shorter OS despite of the heterogeneity between countries (in subgroup of South Korea and Taiwan, HR = 1.34, 95% CI: 1.18-1.53, P < .001; in subgroup of other countries, HR = 2.43, 95% CI: 2.03-2.91, P < .001). The pooled analysis of PFS showed great heterogeneity (I = 79%). All the reported characteristics did not account for the heterogeneity. However, 2 subgroups could be obtained through sensitivity analysis. In one subgroup, patients with BIM deletion polymorphism had shorter PFS (HR = 2.03, 95% CI: 1.71-2.40, P < .001), while in the other subgroup, no significant difference was observed (HR = 0.92, 95% CI: 0.79-1.06, P = .25).
CONCLUSION: NSCLC patients with BIM deletion polymorphism show poor ORR, DCR, and OS after EGFR-TKIs treatment. BIM deletion polymorphism indicates poor response to EGFR-TKIs, and it could be used as a predictor to identify those who would benefit from EGFR-TKIs in NSCLC patients.

Wang F, Diao XY, Zhang X, et al.
Identification of genetic alterations associated with primary resistance to EGFR-TKIs in advanced non-small-cell lung cancer patients with EGFR sensitive mutations.
Cancer Commun (Lond). 2019; 39(1):7 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Identification of activated epidermal growth factor receptor (EGFR) mutations and application of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have greatly changed the therapeutic strategies of non-small-cell lung cancer (NSCLC). However, the long-term efficacy of EGFR-TKI therapy is limited due to the development of drug resistance. The aim of this study was to investigate the correlation between the aberrant alterations of 8 driver genes and the primary resistance to EGFR-TKIs in advanced NSCLC patients with activated EGFR mutations.
METHODS: We retrospectively reviewed the clinical data from 416 patients with stage III/IV or recurrent NSCLC who received an initial EGFR-TKI treatment, from April 2004 and March 2011, at the Sun Yat-sen University Cancer Center. Several genetic alterations associated with the efficacy of EGFR-TKIs, including the alterations in BIM, ALK, KRAS, PIK3CA, PTEN, MET, IGF1R, and ROS1, were detected by the routine clinical technologies. The progression-free survival (PFS) and overall survival (OS) were compared between different groups using Kaplan-Meier survival analysis with the log-rank test. A Cox regression model was used to estimate multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (95% CIs) associated with the PFS and OS.
RESULTS: Among the investigated patients, 169 NSCLC patients harbored EGFR-sensitive mutations. EGFR-mutant patients having PTEN deletion had a shorter PFS and OS than those with intact PTEN (P = 0.003 for PFS, and P = 0.034 for OS). In the combined molecular analysis of EGFR signaling pathway and resistance genes, we found that EGFR-mutant patients coexisted with aberrant alterations in EGFR signaling pathway and those having resistant genes had a statistically poorer PFS than those without such alterations (P < 0.001). A Cox proportional regression model determined that PTEN deletion (HR = 4.29,95% CI = 1.72-10.70) and low PTEN expression (HR = 1.96, 95% CI = 1.22-3.13), MET FISH + (HR = 2.83,95% CI = 1.37-5.86) were independent predictors for PFS in patients with EGFR-TKI treatment after adjustment for multiple factor.
CONCLUSIONS: We determined that the coexistence of genetic alterations in cancer genes may explain primary resistance to EGFR-TKIs.

Meerson A, Eliraz Y, Yehuda H, et al.
Obesity impacts the regulation of miR-10b and its targets in primary breast tumors.
BMC Cancer. 2019; 19(1):86 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Obesity increases breast cancer (BC) risk in post-menopausal women by mostly unknown molecular mechanisms which may partly be regulated by microRNAs (miRNAs).
METHODS: We isolated RNA from paired benign and malignant biopsies from 83 BC patients and determined miRNA profiles in samples from 12 women at the extremes of the BMI distribution by RNA-seq. Candidates were validated in all samples. Associations between miR-10b expression and validated target transcript levels, and effects of targeted manipulation of miR-10b levels in a primary BC cell line on proliferation and invasion potential, were explored.
RESULTS: Of the 148 miRNAs robustly expressed in breast tissues, the levels of miR-21, miR-10b, miR-451a, miR-30c, and miR-378d were significantly associated with presence of cancer. Of these, miR-10b showed a stronger down-regulation in the tumors of the obese subjects, as opposed to the lean. In ductal but not lobular tumors, significant inverse correlations were observed between the tumor levels of miR-10b and miR-30c and the mRNA levels of cancer-relevant target genes SRSF1, PIEZO1, MAPRE1, CDKN2A, TP-53 and TRA2B, as well as tumor grade. Suppression of miR-10b levels in BT-549 primary BC-derived cells increased cell proliferation and invasive capacity, while exogenous miR-10b mimic decreased invasion. Manipulation of miR-10b levels also inversely affected the mRNA levels of miR-10b targets BCL2L11, PIEZO1 and NCOR2.
CONCLUSIONS: Our findings suggest that miR-10b may be a mediator between obesity and cancer in post-menopausal women, regulating several known cancer-relevant genes. MiR-10b expression may have diagnostic and therapeutic implications for the incidence and prognosis of BC in obese women.

Khaw-On P, Pompimon W, Banjerdpongchai R
Apoptosis Induction via ATM Phosphorylation, Cell Cycle Arrest, and ER Stress by Goniothalamin and Chemodrugs Combined Effects on Breast Cancer-Derived MDA-MB-231 Cells.
Biomed Res Int. 2018; 2018:7049053 [PubMed] Free Access to Full Article Related Publications
Goniothalamin (GTN), a styryl-lactone, exhibits inhibitory effects on many kinds of cancer cells

Hu JQ, Deng F, Hu XP, et al.
Histone deacetylase SIRT6 regulates chemosensitivity in liver cancer cells via modulation of FOXO3 activity.
Oncol Rep. 2018; 40(6):3635-3644 [PubMed] Free Access to Full Article Related Publications
Liver cancer is the leading cause of cancer‑related mortality worldwide and its incidence is increasing. Considerable effort has been made in recent decades to improve the diagnosis and treatment of liver cancer. Advanced liver cancer often exhibits a poor response to chemotherapy and poor prognosis due to acquired chemoresistance and tumor recurrence. Understanding the precise molecular mechanisms that are responsible for chemotherapeutic drug‑induced cell death could potentially identify novel therapeutic targets and improve liver cancer treatment. In the present study, it was demonstrated that in response to doxorubicin, the most frequently used chemical compound for liver cancer treatment, histone deacetylase sirtuin 6 (SIRT6) is specifically downregulated. This enables forkhead box O3 (FOXO3) upregulation, translocation into the nucleus and increased expression of its target genes p27 and Bim, which further induce apoptosis. Overexpression of SIRT6, but not enzyme‑inactivated mutants, prevents FOXO3 translocation into the nucleus and doxorubicin‑induced cell death. SIRT6 interacts with FOXO3 and this interaction increases FOXO3 ubiquitination and decreases its stability. Finally, it was identified that the effect of SIRT6 in preventing doxorubicin‑induced cell death requires FOXO3. Overexpression of SIRT6 could not prevent doxorubicin‑induced cell death in FOXO3‑knockdown cells. Therefore, it was concluded that SIRT6 plays a central role in determining doxorubicin‑induced cell death via modulation of FOXO3 activity. Therapeutic targeting of SIRT6 and/or FOXO3 may offer novel strategies for treatment of liver cancer.

Alvarez MC, Maso V, Torello CO, et al.
The polyphenol quercetin induces cell death in leukemia by targeting epigenetic regulators of pro-apoptotic genes.
Clin Epigenetics. 2018; 10(1):139 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In the present study, we investigated the molecular mechanisms underlying the pro-apoptotic effects of quercetin (Qu) by evaluating the effect of Qu treatment on DNA methylation and posttranslational histone modifications of genes related to the apoptosis pathway. This study was performed in vivo in two human xenograft acute myeloid leukemia (AML) models and in vitro using HL60 and U937 cell lines.
RESULTS: Qu treatment almost eliminates DNMT1 and DNMT3a expression, and this regulation was in part STAT-3 dependent. The treatment also downregulated class I HDACs. Furthermore, treatment of the cell lines with the proteasome inhibitor, MG132, together with Qu prevented degradation of class I HDACs compared to cells treated with Qu alone, indicating increased proteasome degradation of class I HDACS by Qu. Qu induced demethylation of the pro-apoptotic BCL2L11, DAPK1 genes, in a dose- and time-dependent manner. Moreover, Qu (50 μmol/L) treatment of cell lines for 48 h caused accumulation of acetylated histone 3 and histone 4, resulting in three- to ten fold increases in the promoter region of DAPK1, BCL2L11, BAX, APAF1, BNIP3, and BNIP3L. In addition, Qu treatment significantly increased the mRNA levels of all these genes, when compared to cells treated with vehicle only (control cells) (*p < 0.05).
CONCLUSIONS: In summary, our results showed that enhanced apoptosis, induced by Qu, might be caused in part by its DNA demethylating activity, by HDAC inhibition, and by the enrichment of H3ac and H4ac in the promoter regions of genes involved in the apoptosis pathway, leading to their transcription activation.

Liu Y, Mondello P, Erazo T, et al.
NOXA genetic amplification or pharmacologic induction primes lymphoma cells to BCL2 inhibitor-induced cell death.
Proc Natl Acad Sci U S A. 2018; 115(47):12034-12039 [PubMed] Free Access to Full Article Related Publications
Although diffuse large B cell lymphoma (DLBCL) cells widely express the BCL2 protein, they rarely respond to treatment with BCL2-selective inhibitors. Here we show that DLBCL cells harboring PMAIP1/NOXA gene amplification were highly sensitive to BCL2 small-molecule inhibitors. In these cells, BCL2 inhibition induced cell death by activating caspase 9, which was further amplified by caspase-dependent cleavage and depletion of MCL1. In DLBCL cells lacking NOXA amplification, BCL2 inhibition was associated with an increase in MCL1 protein abundance in a BIM-dependent manner, causing a decreased antilymphoma efficacy. In these cells, dual inhibition of MCL1 and BCL2 was required for enhanced killing. Pharmacologic induction of NOXA, using the histone deacetylase inhibitor panobinostat, decreased MCL1 protein abundance and increased lymphoma cell vulnerability to BCL2 inhibitors in vitro and in vivo. Our data provide a mechanistic rationale for combination strategies to disrupt lymphoma cell codependency on BCL2 and MCL1 proteins in DLBCL.

Chen G, Chen W, Ye M, et al.
TRIM59 knockdown inhibits cell proliferation by down-regulating the Wnt/β-catenin signaling pathway in neuroblastoma.
Biosci Rep. 2019; 39(1) [PubMed] Free Access to Full Article Related Publications
Neuroblastoma is the most common tumor in children, with a very poor prognosis. It is urgent to identify novel biomarkers to treat neuroblastoma, together with surgery, chemotherapy, and radiation. Human tripartite motif 59 (TRIM59), a member of the TRIM family, has been reported to participate in several human tumors. However, the exact role of TRIM59 in neuroblastoma is unknown. In the present study, real-time PCR and Western blot were used to measure mRNA and protein levels of TRIM59 in four neuroblastoma cell lines and in neuroblastoma tissues. Lentiviruses targeting TRIM59 were used to up/down-regulate TRIM59 expression levels. Cell Counting Kit-8 and Annexin-V/PI were used to analyze cell proliferation and apoptosis in neuroblastoma cell lines. Our data showed that TRIM59 knockdown inhibits cell proliferation while inducing apoptosis in SH-SY5Y and SK-N-SH neuroblastoma cell lines. TRIM59 knockdown up-regulated expression of Bax and Bim and down-regulated levels of Survivin, β-catenin, and c-myc. Interestingly, the inhibition of cell proliferation caused by TRIM59 knockdown could be blocked by LiCl, which is an agonist of Wnt/β-catenin signaling pathway. In contrast, TRIM59 overexpression could increase cell proliferation, up-regulate Survivin, β-catenin and c-myc, down-regulate Bax and Bim, and these effects could be blocked by XAV939, which is an inhibitor of Wnt/β-catenin signaling pathway. In addition, TRIM59 was up-regulated and positively related with β-catenin in neuroblastoma tissues. In conclusion, TRIM59 was up-regulated in neuroblastoma, and TRIM59 knockdown inhibited cell proliferation by down-regulating the Wnt/β-catenin signaling pathway in neuroblastoma.

Vallet S, Fan F, Malvestiti S, et al.
Rationally derived drug combinations with the novel Mcl-1 inhibitor EU-5346 in breast cancer.
Breast Cancer Res Treat. 2019; 173(3):585-596 [PubMed] Related Publications
PURPOSE: Recent studies have emphasized a key role for the anti-apoptotic Bcl-2 family member Mcl-1 in conferring tumor cell survival and drug resistance in breast cancer (BC). Mcl-1 inhibitors, such as the BH3-mimetic EU-5346, therefore represent an exciting new class of targeting agents and are a current focus of widespread cancer-drug development efforts.
METHODS: ONCOMINE analysis was utilized to compare expression profiles of Bcl-2 family members across all major BC subgroups. Potential toxicities of EU-5346 were evaluated using iPS-generated cardiomyocytes, blood cells and astrocytes. The anti-BC cell activity of EU-5346-based therapies was evaluated using [
RESULTS: We previously demonstrated significant anti-tumor activity of EU-5346 in all BC subtypes. Our present results go further and suggest that EU-5346 may induce limited adverse events such as cardiotoxicity, hematotoxicity, and neurotoxicity, frequently observed with other BH3 mimetics. As demonstrated by our mathematical scoring model, the prediction of EU-5643-induced IC
CONCLUSION: These data strongly support the further clinical development of EU-5346 to improve BC patient survival.

Pagano MA, Tibaldi E, Molino P, et al.
Mitochondrial apoptosis is induced by Alkoxy phenyl-1-propanone derivatives through PP2A-mediated dephosphorylation of Bad and Foxo3A in CLL.
Leukemia. 2019; 33(5):1148-1160 [PubMed] Related Publications
Protein phosphatase 2 A (PP2A) is a tumour suppressor whose strong inhibition underlies the phosphorylation-dependent, anti-apoptotic mechanisms in Chronic Lymphocytic Leukemia (CLL). Inactivation of PP2A is due to the cooperative action of the phosphorylation of Y307 of its catalytic subunit by the aberrant cytosolic pool of the Src Family Kinase Lyn and the interaction with its protein inhibitor SET, which is overexpressed in CLL. In this study, we developed a library of compounds, the most potent being the one named CC11, which restores PP2A activity by disrupting the PP2A/SET complex, thereby triggering the mitochondrial pathway of apoptosis. This process involves the recruitment of the pro-apoptotic BH3-only proteins Bad and Bim to mitochondria, the former upon direct dephosphorylation and the latter being newly expressed upon dephosphorylation and activation of its transcription factor FoxO3a. These findings highlight that PP2A antagonizes the prosurvival pathways controlled by Akt, which phosphorylates and thereby suppresses a variety of pro-apoptotic factors and tumour suppressors including Bad and FoxO3a. Furthermore, the PP2A-mediated pro-apoptotic effect of CC11 is synergistically potentiated by the abrogation of Lyn's activity. Our results show that CC11 represents a promising lead compound for a new therapeutic rationale aimed at abrogating the aberrant oncogenic signals in CLL.

Wang-Bishop L, Chen Z, Gomaa A, et al.
Inhibition of AURKA Reduces Proliferation and Survival of Gastrointestinal Cancer Cells With Activated KRAS by Preventing Activation of RPS6KB1.
Gastroenterology. 2019; 156(3):662-675.e7 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND & AIMS: Activation of KRAS signaling and overexpression of the aurora kinase A (AURKA) are often detected in luminal gastrointestinal cancers. We investigated regulation of ribosomal protein S6 kinase B1 (RPS6KB1) by AURKA and the effects of alisertib, an AURKA inhibitor, in mice xenograft tumors grown from human gastrointestinal cancer cells with mutant, activated forms of KRAS.
METHODS: We tested the effects of alisertib or AURKA overexpression or knockdown in 10 upper gastrointestinal or colon cancer cell lines with KRAS mutations or amplifications using the CellTiter-Glo luminescence and clonogenic cell survival assays. We used the proximity ligation in situ assay to evaluate protein co-localization and immunoprecipitation to study protein interactions. Nude mice with xenograft tumors grown from HCT116, SNU-601, SW480, or SNU-1 cells were given oral alisertib (40 mg/kg, 5 times/wk) for 4 weeks. Tumor samples were collected and analyzed by immunoblots and immunohistochemistry. Tissue microarrays from 151 paraffin-embedded human colon tumors, with adjacent normal and adenoma tissues, were analyzed by immunohistochemistry for levels of AURKA.
RESULTS: Alisertib reduced proliferation and survival of the cell lines tested. AURKA knockdown or inhibition with alisertib reduced levels of phosphorylated RPS6KB1 (at T389) and increased levels of proteins that induce apoptosis, including BIM, cleaved PARP, and cleaved caspase 3. AURKA co-localized and interacted with RPS6KB1, mediating RPS6KB1 phosphorylation at T389. We detected AURKA-dependent phosphorylation of RPS6KB1 in cell lines with mutations in KRAS but not in cells with wild-type KRAS. Administration of alisertib to mice with xenograft tumors significantly reduced tumor volumes (P < .001). Alisertib reduced phosphorylation of RPS6KB1 and Ki-67 and increased levels of cleaved caspase 3 in tumor tissues. In analyses of tissue microarrays, we found significant overexpression of AURKA in gastrointestinal tumor tissues compared with non-tumor tissues (P = .0003).
CONCLUSION: In studies of gastrointestinal cancer cell lines with activated KRAS, we found AURKA to phosphorylate RPS6KB1, promoting cell proliferation and survival and growth of xenograft tumors in mice. Agents that inhibit AURKA might slow the growth of gastrointestinal tumors with activation of KRAS.

Saitoh Y, Bureta C, Sasaki H, et al.
The histone deacetylase inhibitor LBH589 inhibits undifferentiated pleomorphic sarcoma growth via downregulation of FOS-like antigen 1.
Mol Carcinog. 2019; 58(2):234-246 [PubMed] Related Publications
Undifferentiated pleomorphic sarcoma (UPS) is the second most frequent soft tissue sarcoma. Because of its resistance to chemotherapy, UPS patients are treated with surgical resection and complementary radiotherapy. However, since standard chemotherapy has not been established, unresectable or metastatic cases result in a poor prognosis. Therefore, the identification of a more effective therapy for UPS patients is needed. The development and progression of malignant tumors involve epigenetic alterations, and histone deacetylases (HDAC) have become a promising chemotherapeutic target. In this study, we investigated the potential effects and mechanisms of an HDAC inhibitor, LBH589, in UPS cells. We confirmed that LBH589 exhibits potent antitumor activities in four human UPS cell lines (GBS-1, TNMY-1, Nara-F, and Nara-H) and IC

Mashimo K, Tsubaki M, Takeda T, et al.
RANKL-induced c-Src activation contributes to conventional anti-cancer drug resistance and dasatinib overcomes this resistance in RANK-expressing multiple myeloma cells.
Clin Exp Med. 2019; 19(1):133-141 [PubMed] Related Publications
The survival and growth of multiple myeloma (MM) cells are facilitated by cell-cell interactions with bone marrow stromal cells and the bone marrow microenvironment. These interactions induce de novo drug resistance known as cell adhesion-mediated drug resistance. Our previous results recently revealed that the receptor activator of NF-κB (RANK) ligand (RANKL), which is expressed by bone marrow stromal cells, contributes to anti-cancer drug resistance through the activation of various signaling molecules and suppression of Bim expression in RANK-expressing MM cells. However, the detailed mechanisms underlying RANKL-induced drug resistance remain uncharacterized. In the present study, we investigated the mechanism of RANKL-induced drug resistance in RANK-expressing MM cell lines. We found treatment of MM cells with RANKL-induced c-Src phosphorylation and activation of the downstream signaling molecules Akt, mTOR, STAT3, JNK, and NF-κB. In addition, treatment with dasatinib, a c-Src inhibitor, overcame RANKL- and bone marrow stromal cell-induced drug resistance to adriamycin, vincristine, dexamethasone, and melphalan by suppressing c-Src, Akt, mTOR, STAT3, JNK, and NF-κB activation and enhancing expression of Bim. Overall, RANKL- and bone marrow stromal cell-induced drug resistance correlated with the activation of c-Src signaling pathways, which caused a decrease in Bim expression. Dasatinib treatment of RANK-expressing MM cells re-sensitized them to anti-cancer drugs. Therefore, inhibition of c-Src may be a new therapeutic approach for overcoming RANKL-induced drug resistance in patients with MM.

Lin J, Cao Y, Yu L, Lin L
Non-α-fetoprotein-producing adrenal hepatoid adenocarcinoma: A case report and literature review.
Medicine (Baltimore). 2018; 97(39):e12336 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
RATIONALE: Adrenal hepatoid adenocarcinoma typically secretes alpha-fetoprotein (AFP). Here, we report a case of non-AFP-producing adrenal hepatoid adenocarcinoma. Next-generation sequencing (NGS) was conducted to identify gene mutations.
PATIENT CONCERNS: A 64-year-old man presented with mild back pain and unexplained weight loss for 3 months.
DIAGNOSES: Contrast-enhanced magnetic resonance imaging (MRI) showed a mass (9.9 × 9.7 × 9.1 mm) above the upper pole of the left kidney. The left renal artery and vein were compressed. The tumor was positive for CK8/18, CK19, CK7, hepatocyte marker (Hepatocyte), and Hep Par 1, but negative for AFP. Plasma AFP was 2.75 ng/mL (normal range: 0-7 ng/mL). NGS revealed mutations of the following genes: ATM, CDKN2A, EGFR, STK11, TP53, BIM, and MLH1. A diagnosis of adrenal hepatoid adenocarcinoma was established.
INTERVENTIONS: The treatment included 4 cycles of the mFOLFOX6 regimen (oxaliplatin, leucovorin, and fluorouracil), transcatheter arterial chemoembolization, and apatinib.
OUTCOMES: The patient died 9 months after the diagnosis.
LESSONS: This case highlights the importance of thorough clinical, radiological, and immunohistochemical investigation for suspected adrenal hepatoid adenocarcinoma. Metastasis from other primary tumors should be ruled out. Furthermore, AFP is not necessarily elevated in adrenal hepatoid adenocarcinoma. NGS could be helpful in establishing the diagnosis and selecting treatments.

Talib WH, Al Kury LT
Parthenolide inhibits tumor-promoting effects of nicotine in lung cancer by inducing P53 - dependent apoptosis and inhibiting VEGF expression.
Biomed Pharmacother. 2018; 107:1488-1495 [PubMed] Related Publications
The correlation between cigarette smoking and the onset of non-small cell lung cancer is well documented. Enhanced proliferation, angiogenesis induction, and resistance to apoptosis were reported as direct results associated with exposure to nicotine (the active ingredient of cigarettes). Parthenolide is a sesquiterpene lactone with anticancer activity against different cancer types. In this study, we tested the ability of parthenolide to inhibit the proliferating effect of nicotine in lung cancer cell lines. MTT assay was used to measure cell survival of A549 and H526 cells treated with nicotine, parthenolide, and their combination. Angiogenesis inhibition was measured using VEGF detection kit and apoptosis induction was evaluated by measuring caspase-3 activity. Real time PCR assay was used to detect the change in expression of several genes associated with cell proliferation and apoptosis (CASP3, CASP7, CASP8, CASP9, P53, GADD45, BAX, BIM, Bcl-2, TOPO I, and TOPO II). Parthenolide inhibited lung cancer cells in a concentration-dependent manner and decreased the proliferation stimulating effect of nicotine. Caspase-3 activity and VEGF assays evidenced an apoptosis-inducing and VEGF- inhibiting effects of parthenolide. The real time PCR assay demonstrated that parthenolide down-regulated the expression of Bcl-2 and up-regulated the expression of E2F1, P53, GADD45, BAX, BIM, and CASP 3,7,8,9, which indicates an activation of P53- dependent apoptosis pathway in response to parthenolide. Furthermore, this pathway remained active in the presence of nicotine suggesting the ability of parthenolide to exclude the anti-apoptotic effect of nicotine. Our results indicate that parthenolide inhibits nicotine proliferating effect on lung cancer. The anticancer effect of parthenolide is mediated by angiogenesis inhibition and activation of P53- dependent apoptosis. Parthenolide is a promising natural product for inhibiting and treating nicotine-associated lung cancer. However, further studied on more lung cancer cell lines and on protein level are needed to fully understand its mechanisms of action.

Jang B, Kim LH, Lee SY, et al.
Trichostatin A induces apoptosis in oral squamous cell carcinoma cell lines independent of hyperacetylation of histones.
J Cancer Res Ther. 2018; 14(Supplement):S576-S582 [PubMed] Related Publications
Aim of Study: To investigate the apoptotic event of trichostatin A (TSA) and its associated mechanism in oral squamous cell carcinoma (OSCC) lines.
Materials and Methods: HSC-3 and Ca9.22 cell lines were evaluated using a trypan blue exclusion assay, histone isolation, soft agar assay, live/dead assay, 4%,6-diamidino-2-phenylindole staining, JC-1 mitochondrial membrane potential (MMP) assay, and Western blot analysis to demonstrate the anticancer activity of TSA.
Results: TSA decreased OSCC cell viability and proliferation without affecting the histone acetylation. TSA-induced caspase-dependent or -independent apoptosis according to cell types, TSA enhanced the expression levels of Bim protein by dephosphorylating ERK1/2 pathway in HSC-3 cells. TSA also damaged MMP and increased cytosolic apoptosis-inducing factor (AIF) in Ca9.22 cells.
Conclusion: The present study suggests that TSA may be a potential anticancer drug candidate for the treatment of OSCC through the induction of apoptosis.

Yao Y, Chu H, Wang J, Wang B
Decreased human antigen R expression confers resistance to tyrosine kinase inhibitors in epidermal growth factor receptor-mutant lung cancer by inhibiting Bim expression.
Int J Mol Med. 2018; 42(5):2930-2942 [PubMed] Related Publications
Primary resistance to epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs) is an obstacle for the treatment of non‑small cell lung cancer (NSCLC); however, the associated mechanisms are not well understood. Studies have reported that Bim expression levels may be associated with the efficacy of EGFR‑TKI treatment in NSCLC patients harboring EGFR mutations. Human antigen R (HuR) regulates the mRNA and protein expression of target genes, including certain B‑cell lymphoma 2 family members. The present study investigated whether HuR mediates resistance to EGFR‑TKIs via the regulation of Bim. The results demonstrated that decreased levels of HuR and Bim protein expression are associated with primary resistance to EGFR‑TKIs and reduced median progression‑free survival in NSCLC patients. In vitro assays also revealed that knockdown of HuR resulted in primary EGFR‑TKI resistance and reduced gefitinib‑induced apoptosis in HCC827 cells by decreasing Bim expression. Furthermore, elevated HuR expression restored gefitinib sensitivity and enhanced gefitinib‑induced apoptosis in H1650 cells by increasing Bim expression. In vivo, it was further demonstrated that overexpression of HuR was able to restore the gefitinib sensitivity of H1650 cells. Therefore, altered HuR/Bim expression is proposed to be a novel mechanism of EGFR‑TKI resistance in NSCLC.

Matuszcak C, Lindner K, Eichelmann AK, et al.
microRNAs: Key regulators of chemotherapy response and metastatic potential via complex control of target pathways in esophageal adenocarcinoma.
Surg Oncol. 2018; 27(3):392-401 [PubMed] Related Publications
INTRODUCTION: Incidence of esophageal adenocarcinoma (EAC) increased significantly over the last decades. Lack of response to chemotherapy is a major problem in the treatment of this disease. This study aims to assess the biological relevance of characteristic microRNA profiles of chemotherapy resistant EAC cells with regards to response to chemotherapy and biological behavior.
METHODS: We selected 3 microRNAs from characteristic microRNA profiles of resistant EAC (miR-27b-3p, miR-200b-3p, and miR-148a-3p). Expression of microRNAs was modified in 6 EAC cell lines. Effects on chemotherapy, adhesion, migration, apoptosis and cell cycle were assessed using standard assays. Target analyses were performed using Western Blot and Luciferase techniques.
RESULTS: MiR-27b-3p significantly sensitized cells to 5FU and Cisplatin in 83% respectively in 33% of cell lines, miR-148a-3p in 67% respectively 33% of cases. MiR-200b-3p increased sensitivity only towards 5FU in 50% of cases. Co-transfections with miR-27b-3p/miR-148a-3p showed an additive effect on response to chemotherapy in 50% of cases. Upregulation of miR-148a-3p reduced protein expression levels of DNMT-1, MSK-1, Bcl-2 and Bim, and miR-27b upregulation led to downregulation of Sp1 and PPARy proteins implicating a potential negative post-transcriptional control via the respective microRNAs. Finally, we were able to confirm Bcl-2 for the first time as direct target of miR-148a-3p in EAC.
CONCLUSION: This study demonstrates that specific microRNA profiles of chemotherapy resistant EAC in fact determine their response to chemotherapy and biological behavior. Our data further show that microRNA-mediated regulation of chemotherapy resistance is complex, and several microRNAs seem to "co-operate" at various steps within a broad number of pathways what fits very well to our recently proposed understanding of microRNA-mediated regulation as function of cellular functional complexes. These data highlight the promising potential of microRNAs to predict or monitor treatment response to chemotherapy in EAC, and to potentially modulate tumor biology in a therapeutic approach.

Yochum ZA, Cades J, Wang H, et al.
Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer.
Oncogene. 2019; 38(5):656-670 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) have significantly benefited from the use of EGFR tyrosine kinase inhibitors (TKIs). However, long-term efficacy of these therapies is limited due to de novo resistance (~30%) as well as acquired resistance. Epithelial-mesenchymal transition transcription factors (EMT-TFs), have been identified as drivers of EMT-mediated resistance to EGFR TKIs, however, strategies to target EMT-TFs are lacking. As the third generation EGFR TKI, osimertinib, has now been adopted in the first-line setting, the frequency of T790M mutations will significantly decrease in the acquired resistance setting. Previously less common mechanisms of acquired resistance to first generation EGFR TKIs including EMT are now being observed at an increased frequency after osimertinib. Importantly, there are no other FDA approved targeted therapies after progression on osimertinib. Here, we investigated a novel strategy to overcome EGFR TKI resistance through targeting the EMT-TF, TWIST1, in EGFR-mutant NSCLC. We demonstrated that genetic silencing of TWIST1 or treatment with the TWIST1 inhibitor, harmine, resulted in growth inhibition and apoptosis in EGFR-mutant NSCLC. TWIST1 overexpression resulted in erlotinib and osimertinib resistance in EGFR-mutant NSCLC cells. Conversely, genetic and pharmacological inhibition of TWIST1 in EGFR TKI-resistant EGFR-mutant cells increased sensitivity to EGFR TKIs. TWIST1-mediated EGFR TKI resistance was due in part to TWIST1 suppression of transcription of the pro-apoptotic BH3-only gene, BCL2L11 (BIM), by directly binding to BCL2L11 intronic regions and promoter. As such, pan-BCL2 inhibitor treatment overcame TWIST1-mediated EGFR TKI resistance and were more effective in the setting of TWIST1 overexpression. Finally, in a mouse model of autochthonous EGFR-mutant lung cancer, Twist1 overexpression resulted in erlotinib resistance and suppression of erlotinib-induced apoptosis. These studies establish TWIST1 as a driver of resistance to EGFR TKIs and provide rationale for use of TWIST1 inhibitors or BCL2 inhibitors as means to overcome EMT-mediated resistance to EGFR TKIs.

Fujiwara H, Tateishi K, Kato H, et al.
Isocitrate dehydrogenase 1 mutation sensitizes intrahepatic cholangiocarcinoma to the BET inhibitor JQ1.
Cancer Sci. 2018; 109(11):3602-3610 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Cholangiocarcinoma is a life-threatening disease with a poor prognosis. Although genome analysis unraveled some genetic mutation profiles in cholangiocarcinoma, it remains unknown whether such genetic abnormalities relate to the effects of anticancer drugs. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are exclusively found in almost 20% of intrahepatic cholangiocarcinoma (ICC). Recently, the anticancer effects of BET inhibitors including JQ1 have been shown in various tumors. In the present study, we report that the antigrowth effect of JQ1 differs among ICC cells and IDH1 mutation sensitizes ICC cells to JQ1. RBE cells harboring IDH1 mutation was more sensitive to JQ1 than HuCCT1 or HuH28 cells with wild-type IDH1. JQ1 induced apoptosis only in RBE cells through the upregulation of proapoptotic genes BAX and BIM. We found that the antigrowth effect was not attributed to downregulation of the MYC gene as a well-known target of JQ1 in various cancer cells. Notably, the forced expression of mutant IDH1 successfully sensitized HuCCT1 cells to JQ1. In addition, AGI-5198, a selective inhibitor of mutant IDH1 partially reversed the decrease in viability after JQ1 treatment and also suppressed the JQ1-induced apoptosis in RBE cells. These data suggest that IDH1 mutation contributed to the growth inhibitory effect of JQ1 in RBE cells. Furthermore, given that the effect of mutant IDH1 was not recapitulated in glioblastoma cells, the enhancement of JQ1 sensitivity by IDH1 mutation seems to be specific for ICC cells. Our findings propose a new stratified therapeutic strategy based on IDH1 mutation in ICC.

Zhou Y, Liu H, Xue R, et al.
BH3 Mimetic ABT-199 Enhances the Sensitivity of Gemcitabine in Pancreatic Cancer in vitro and in vivo.
Dig Dis Sci. 2018; 63(12):3367-3375 [PubMed] Related Publications
BACKGROUND AND AIMS: Pancreatic cancer is an aggressive malignancy with poor prognosis. Gemcitabine is the standard chemotherapeutic drug used to treat the disease; however, it has a low response rate. Therefore, there is an urgent need to develop new and safe therapies to enhance sensitivity to gemcitabine in treating pancreatic cancer.
METHODS: The synergistic effect of gemcitabine combined with specific B cell CLL/lymphoma 2 (Bcl-2) inhibitor ABT-199 against pancreatic cancer was tested using cell viability, cell cycle, and apoptosis assays in vitro and in an MIA Paca-2 xenograft model in vivo. Its underlying mechanism was explored using western blotting analysis of Bcl-2 family proteins.
RESULTS: ABT-199 not only enhanced the effect of gemcitabine on cell growth inhibition but also promoted gemcitabine-induced apoptosis in pancreatic cancer cell lines. Gemcitabine decreased the expression of anti-apoptotic protein Mcl-1 but increased the expression of anti-apoptotic protein Bcl-2. ABT-199 downregulated the gemcitabine-induced production of Bcl-2 and increased the expression of pro-apoptotic protein Bcl-2 interacting protein (BIM). Mouse xenograft experiments also confirmed the synergistic effect of gemcitabine and ABT-199 on tumor growth inhibition and the induction of tumor cell apoptosis.
CONCLUSION: Our results indicated that ABT-199 improved the anti-tumor effect of gemcitabine on pancreatic cancer by downregulating gemcitabine-induced overexpression of Bcl-2. ABT-199 has already been investigated in phase 3 clinical trials for chronic lymphocytic leukemia; therefore, it may serve as a potential drug to improve the sensitivity of pancreatic cancer to gemcitabine.

Ngai H, Tian G, Courtney AN, et al.
IL-21 Selectively Protects CD62L
J Immunol. 2018; 201(7):2141-2153 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
T cells expressing CD19-specific chimeric Ag receptors (CARs) produce high remission rates in B cell lymphoma, but frequent disease recurrence and challenges in generating sufficient numbers of autologous CAR T cells necessitate the development of alternative therapeutic effectors. Vα24-invariant NKTs have intrinsic antitumor properties and are not alloreactive, allowing for off-the-shelf use of CAR-NKTs from healthy donors. We recently reported that CD62L

Qin Y, Li L, Wang F, et al.
Knockdown of Mir-135b Sensitizes Colorectal Cancer Cells to Oxaliplatin-Induced Apoptosis Through Increase of FOXO1.
Cell Physiol Biochem. 2018; 48(4):1628-1637 [PubMed] Related Publications
BACKGROUND/AIMS: Aberrant expression of microRNAs (miRNAs) is found to be responsible for tumorigenesis, cancer development and chemoresistance. Although oxaliplatin is an effective chemotherapeutic drug for treatment of colorectal cancer (CRC), CRC cells can develop some mechanisms to evade oxaliplatin-induced cell death. It is urgent to explore the novel strategies to increase the chemosensitivity of CRC cells.
METHODS: QRT-PCR analysis was performed to detect the expression of miR-135b in CRC patients' serum and CRC cell lines. MTT assays were used to evaluate the effect of anti-miR-135b on oxaliplatin-induced cell death in CRC cell lines. Western blot, flow cytometry and luciferase reporter assays were performed to evaluate the potential mechanism and pathway of anti-miR-135b-promoted apoptosis in oxaliplatin-treated CRC cells.
RESULTS: Significant upregulation of miR-135b was observed in CRC cell lines and CRC patients' serum. Knockdown of miR-135b was found to sensitize colorectal cancer cells to oxaliplatin-induced cytotoxicity. Mechanically, knockdown of miR-135b increased the expression level of FOXO1 in CRC. As the downstream, the increased FOXO1 induced by anti-miR-135b promoted the expression of Bim and Noxa. Since Bim and Noxa act as key pro-apoptotic proteins in mitochondrial apoptosis, anti-miR-135b was able to enhance the oxaliplatin-induced apoptosis dependent on the anti-miR-135b/FOXO1 axis.
CONCLUSIONS: Anti-miR-135b enhanced the anti-tumor effect of oxaliplatin on CRC. Combination with miR-135b antisense nucleotides may represent a novel strategy to sensitize CRC to oxaliplatin-based treatment.

Mogensen MB, Rossing M, Østrup O, et al.
Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing.
BMC Cancer. 2018; 18(1):752 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The search for predictive biomarkers is often performed on primary tumours tissue. In order to assess the effectiveness of tailored treatment in regard to the primary tumour the differences in the genomic profile needs to be clarified.
METHODS: Fresh-frozen tissue from primary tumours, synchronous liver metastases and adjacent normal liver was collected from 21 patients and analysed by whole-exome sequencing on the Illumina HiSeq 2500 platform. Gene variants designated as 'damaging' or 'potentially damaging' by Ingenuity software were used for the subsequent comparative analysis. BAM files were used as the input for the analysis of CNAs using NEXUS software.
RESULTS: Shared mutations between the primary tumours and the synchronous liver metastases varied from 50 to 96%. Mutations in APC, KRAS, NRAS, TP53 or BRAF were concordant between the primary tumours and the metastases. Among the private mutations were well-known driver genes such as PIK3CA and SMAD4. The number of mutations was significantly higher in patients with right- compared to left-sided tumours (102 vs. 66, p = 0.004). Furthermore, right- compared to left-sided tumours had a significantly higher frequency of private mutations (p = 0.023). Similarly, CNAs differed between the primary tumours and the metastases. The difference was mostly comprised of numerical and segmental aberrations. However, novel CNAs were rarely observed in specific CRC-relevant genes.
CONCLUSION: The examined primary colorectal tumours and synchronous liver metastases had multiple private mutations, indicating a high degree of inter-tumour heterogeneity in the individual patient. Moreover, the acquirement of novel CNAs from primary tumours to metastases substantiates the need for genomic profiling of metastases in order to tailor metastatic CRC therapies. As for the mutational status of the KRAS, NRAS and BRAF genes, no discordance was observed between the primary tumours and the metastases.

Liu Z, Huang S, Cao Y, et al.
YAP1 inhibits circRNA-000425 expression and thus promotes oncogenic activities of miR-17 and miR-106.
Biochem Biophys Res Commun. 2018; 503(4):2370-2375 [PubMed] Related Publications
YAP1, a vital effector of Hippo pathway, promotes cancer development via transcriptionally regulating a batch of target genes involved in various signaling pathways, including proliferation, apoptosis, and cell drug sensitivity. Recently, circular RNAs (circRNAs) have been shown to control gene expression post-transcriptionally and become a new layer of gene regulation. However, whether circRNAs play roles in YAP1-induced tumorigenesis is still largely elusive. Here, we identify circRNA-000425 as a new inhibitory target of YAP1, and also find that it binds to miR-17/miR-106b, and thus suppresses cancer cell growth induced by these miRNAs. circRNA-000425 is revealed as a YAP1 target through circRNA microarray analysis of RNAs extracted from cells treated with or without YAP1 siRNAs, and further confirmed by RT-q-PCR and ChIP assays. Interestingly, bioinformatics analysis, luciferase assay, and RT-q-PCR results showed that circRNA-000425 binds to miR-17 and miR-106b, but not let-7a, and rescues the inhibitory effect of miR-17/miR-106 on the expressions of both p21 and BIM. In addition, colony formation and MTT assay showed that circRNA-000425 inhibits cancer cell growth induced by miR-17. These findings reveal a mechanism by which YAP1 promotes oncogenic activities of miR-17 and miR-106b through transcriptionally inhibiting circRNA-000425 expression.

Sun J, Li B, Jia Z, et al.
RUNX3 inhibits glioma survival and invasion via suppression of the β-catenin/TCF-4 signaling pathway.
J Neurooncol. 2018; 140(1):15-26 [PubMed] Related Publications
INTRODUCTION: Runt-related transcription factor 3 (RUNX3) exerts a tumor suppressor gene associated with gastric and other cancers, including glioma. However, how its anti-tumor mechanism in functions glioma is unclear.
METHODS: We assayed expression of RUNX3 with a tissue microarray (TMA), frozen cancer tissues and malignant glioma cell lines using immunohistochemistry, qRT-PCR and Western bolt analysis. Cell proliferation, invasion, cell cycle distribution and apoptosis were also examined to confirm the effect of RUNX3 medicated malignant phenotype. TOP/FOP experiment was used to detect the β-catenin/Tcf-4 transcription activity by RUNX3.
RESULTS: Enforced RUNX3 expression inhibited proliferation and invasion, induced cell cycle arrest and promoted apoptosis in vitro and in vivo, Bim siRNA partically reversed the effect of RUNX3-induced apoptosis in LN229 and U87 cells, suggesting a dependent role of Bim-caspase pathway. Moreover, Mechanism investigations revealed that restoration of RUNX3 suppressed β-catenin/Tcf-4 transcription activity.
CONCLUSIONS: RUNX3 plays a pivotal role in glioma initiation and progression as a tumor suppressor via attenuation of Wnt signaling, highlighting it as a potential therapeutic target for glioma.

Liang W, Liao Y, Li Z, et al.
MicroRNA-644a promotes apoptosis of hepatocellular carcinoma cells by downregulating the expression of heat shock factor 1.
Cell Commun Signal. 2018; 16(1):30 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
In this study, we investigated the role of microRNA-644a (miR-644a) in the growth and survival of hepatocellular carcinoma (HCC) cells. MiR-644a levels were lower in HCC tissues than in adjacent peri-cancerous tissues (n = 135). MiR-644a expression was inversely correlated with heat shock factor 1 (HSF1) expression, tumour diameter and TNM stage. Moreover, HepG2 and SMMC-7721 cell lines showed lower miR-644a expression than normal L-O2 hepatocytes. MiR-644a overexpression in HepG2 and SMMC-7721 cells increased apoptosis by downregulating HSF1. Dual luciferase reporter assays confirmed the presence of a miR-644a binding site in the 3'-untranslated region (3'-UTR) of HSF1. Xenograft tumours derived from SMMC-7721 cells transfected with a miR-664a mimic showed less growth than tumours derived from untransfected controls. Protein chip analysis revealed that miR-644a-overexpressing SMMC-7721 and HepG2 cells strongly expressed pro-apoptotic BH3-only proteins, such as BID, BAD, BIM, SMAC, Apaf-1 and cleaved caspases-3 and -9. These findings suggest miR-644a promotes apoptosis in HCC cells by inhibiting HSF1.

Bai X, Han G, Liu Y, et al.
MiRNA-20a-5p promotes the growth of triple-negative breast cancer cells through targeting RUNX3.
Biomed Pharmacother. 2018; 103:1482-1489 [PubMed] Related Publications
Increasing evidence showed that microRNAs (miRNAs) were abnormally expressed in cancers and made effects on the tumorigenesis. Aberrant expression of miR-20a-5p has been reported in human breast carcinoma. However, the functional mechanism of miR-20a-5p in human breast carcinoma, particularly in triple-negative breast cancer (TNBC), required further investigations. Here, firstly, we determined that miR-20a-5p was highly expressed in both TNBC tissues and cell lines. Then, we explored that the overexpression of miR-20a-5p promoted the migration and invasion of TNBC cells in vitro. The tendency was significantly reversed after the depletion of miR-20a-5p. Consistent result could be obtained with the in vivo nude mice tumorigenesis. Thirdly, the underlying molecular mechanism was investigated. The Runt-related transcription factor 3 (RUNX3) was identified as a target of miR-20a-5p in TNBC cells. High expression of miR-20a-5p significantly decreased both the mRNA and protein levels of RUNX3, as well as its direct downstream targets Bim and p21. These results verified the significance of miR-20a-5p and explored its functional mechanisms in TNBC, suggesting the potential clinical applications of miR-20a-5p in TNBC.

Abdoul-Azize S, Buquet C, Li H, et al.
Integration of Ca
Oncogene. 2018; 37(36):4979-4993 [PubMed] Related Publications
Recent studies have suggested that the lipid-lowering agent simvastatin holds great promise as a cancer therapeutic; it inhibits the growth of multiple tumors, including triple-negative breast cancer. Doxorubicin- and simvastatin-induced cytotoxicity has been associated with the modulation of Ca

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