BCL2L12

Gene Summary

Gene:BCL2L12; BCL2 like 12
Location:19q13.33
Summary:This gene encodes a member of a family of proteins containing a Bcl-2 homology domain 2 (BH2). The encoded protein is an anti-apoptotic factor that acts as an inhibitor of caspases 3 and 7 in the cytoplasm. In the nucleus, it binds to the p53 tumor suppressor protein, preventing its association with target genes. Overexpression of this gene has been detected in a number of different cancers. There is a pseudogene for this gene on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:bcl-2-like protein 12
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
BCL2L12 is implicated in:
- apoptotic process
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 12 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 11 March, 2017 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: BCL2L12 (cancer-related)

Adamopoulos PG, Kontos CK, Tsiakanikas P, Scorilas A
Identification of novel alternative splice variants of the BCL2L12 gene in human cancer cells using next-generation sequencing methodology.
Cancer Lett. 2016; 373(1):119-29 [PubMed] Related Publications
The next-generation sequencing (NGS) technology has enabled genome-wide studies, providing massively parallel DNA sequencing. NGS applications constitute a revolution in molecular biology and genetics and have already paved new ways in cancer research. BCL2L12 is an apoptosis-related gene, previously cloned from members of our research group. Like most members of the BCL2 gene family, it is highly implicated in various types of cancer and hematological malignancies. In the present study, we used NGS to discover novel alternatively spliced variants of the apoptosis-related BCL2L12 gene in many human cancer cell lines, after 3'-RACE nested PCR. Extensive computational analysis uncovered new alternative splicing events and patterns, resulting in novel alternative transcripts of the BCL2L12 gene. PCR was then performed to validate NGS data and identify the derived novel transcripts of the BCL2L12 gene. Therefore, 50 novel BCL2L12 splice variants were discovered. Since BCL2L12 is involved in the apoptotic machinery, the quantification of distinct BCL2L12 transcripts in human samples may have clinical applications in different types of cancer.

Kouri FM, Ritner C, Stegh AH
miRNA-182 and the regulation of the glioblastoma phenotype - toward miRNA-based precision therapeutics.
Cell Cycle. 2015; 14(24):3794-800 [PubMed] Free Access to Full Article Related Publications
Glioblastoma (GBM) is an incurable cancer, with survival rates of just 14-16 months after diagnosis. (1) Functional genomics have identified numerous genetic events involved in GBM development. One of these, the deregulation of microRNAs (miRNAs), has been attracting increasing attention due to the multiple biologic processes that individual miRNAs influence. Our group has been studying the role of miR-182 in GBM progression, therapy resistance, and its potential as GBM therapeutic. Oncogenomic analyses revealed that miR-182 is the only miRNA, out of 470 miRNAs profiled by The Cancer Genome Atlas (TCGA) program, which is associated with favorable patient prognosis, neuro-developmental context, temozolomide (TMZ) susceptibility, and most significantly expressed in the least aggressive oligoneural subclass of GBM. miR-182 sensitized glioma cells to TMZ-induced apoptosis, promoted glioma initiating cell (GIC) differentiation, and reduced tumor cell proliferation via knockdown of Bcl2L12, c-Met and HIF2A. (2) To deliver miR-182 to intracranial gliomas, we have characterized Spherical Nucleic Acids covalently functionalized with miR-182 sequences (182-SNAs). Upon systemic administration, 182-SNAs crossed the blood-brain/blood-tumor barrier (BBB/BTB), reduced tumor burden, and increased animal subject survival. (2-4) Thus, miR-182-based SNAs represent a tool for systemic delivery of miRNAs and a novel approach for the precision treatment of malignant brain cancers.

Tong Z, Liu N, Lin L, et al.
miR-125a-5p inhibits cell proliferation and induces apoptosis in colon cancer via targeting BCL2, BCL2L12 and MCL1.
Biomed Pharmacother. 2015; 75:129-36 [PubMed] Related Publications
MicroRNAs (miRNAs) are small non-coding RNAs that function as regulators of gene expression. MiR-125 is a family of miRNAs that have been shown to be involved in various cancer types. In this study, for the first time, we showed that miR-125a-5p was specifically down-regulated in both colon cancer tissue and colon cancer cell lines. The tumor suppressor role of miR-125a-5p in colon cancer was supported by the observation that overexpression of miR-125a-5p inhibited cell proliferation and induced cell apoptosis in colon cancer cells. We also confirmed that in colon cancer cells, anti-apoptotic genes BCL2, BCL2L12 and Mcl-1 were direct targets of miR-125a-5p, and they were down-regulated by miR-125a-5p overexpression. Furthermore, restoration of BCL2, BCL2L12 and Mcl-1 expression in colon cancer cells could partially reverse the cell proliferation inhibition and apoptosis stimulation caused by miR-125a-5p overexpression, indicating that miR-125a-5p inhibits cell proliferation and induces apoptosis in colon cancer cells via targeting BCL2, BCL2L12 and Mcl-1.

Chien ST, Yang TF, Yang MC, et al.
Differential roles of Bcl2L12 and its short variant in breast cancer lymph node metastasis.
Oncol Rep. 2015; 34(2):961-71 [PubMed] Related Publications
Bcl2L12 plays a role in post-mitochondrial apoptosis through multiple mechanisms involving p53, αB-crystallin, caspase-3 and -7 in glioblastoma. Bcl2L12 is reported to be a good prognostic marker in breast cancer and correlated with ER and Bcl2 expression status. However, the mechanisms by which Bcl2L12 regulates apoptosis in breast cancer (BCa) remain unknown. Recent studies have shown that Bcl2L12 expression is a useful biomarker in other types of cancer. Thus, we examined whether Bcl2L12 and Bcl2L12A mRNA were associated with breast cancer progression or a specific subtype. In total, 106 paraffin-embedded, different stage breast cancer specimens were prepared and quantified for Bcl2L12 and Bcl2L12A expression by PCR. The correlation between Bcl2L12 and Bcl2L12A mRNA levels and clinicopathological characteristics was statistically analyzed. The results showed that Bcl2L12 and Bcl2L12A mRNA expression was not significantly different across the different stage, grade and TNM classification groups (P>0.005). Using linear regression, Bcl2L12 mRNA was associated with Bcl2L12A mRNA, grade 3 tumor and the triple-negative breast cancer (TNBC) subtype. In non-TNBC specimens, Bcl2L12 mRNA was only correlated with Bcl2L12A mRNA. Bcl2L12A mRNA was positively associated with Bcl2L12 mRNA and the number of lymph node metastases, but negatively correlated with staging in the non-TNBC group. Specifically, Bcl2L12, but not Bcl2L12A, mRNA was significantly higher in TNBC and grade 3 tumors, respectively. In non-TNBC, Bcl2L12A mRNA was significantly highly expressed in tumors with ≥ 12 metastatic lymph nodes. Bcl2L12 and its variant mRNA were highly expressed in carcinoma in situ (CIS) samples. In addition, they were estimated to be correlated with the total sample and non-TNBC, but not the TNBC group. In summary, a high Bcl2L12 mRNA expression was associated with the high-grade BCa and TNBC subtype. In addition, the interplay between Bcl2L12 and its variant may be associated with high lymph node metastasis in non-TNBC tumors.

Kouri FM, Hurley LA, Daniel WL, et al.
miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma.
Genes Dev. 2015; 29(7):732-45 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) is a lethal, therapy-resistant brain cancer consisting of numerous tumor cell subpopulations, including stem-like glioma-initiating cells (GICs), which contribute to tumor recurrence following initial response to therapy. Here, we identified miR-182 as a regulator of apoptosis, growth, and differentiation programs whose expression level is correlated with GBM patient survival. Repression of Bcl2-like12 (Bcl2L12), c-Met, and hypoxia-inducible factor 2α (HIF2A) is of central importance to miR-182 anti-tumor activity, as it results in enhanced therapy susceptibility, decreased GIC sphere size, expansion, and stemness in vitro. To evaluate the tumor-suppressive function of miR-182 in vivo, we synthesized miR-182-based spherical nucleic acids (182-SNAs); i.e., gold nanoparticles covalently functionalized with mature miR-182 duplexes. Intravenously administered 182-SNAs penetrated the blood-brain/blood-tumor barriers (BBB/BTB) in orthotopic GBM xenografts and selectively disseminated throughout extravascular glioma parenchyma, causing reduced tumor burden and increased animal survival. Our results indicate that harnessing the anti-tumor activities of miR-182 via safe and robust delivery of 182-SNAs represents a novel strategy for therapeutic intervention in GBM.

Papadopoulos EI, Yousef GM, Scorilas A
Gemcitabine impacts differentially on bladder and kidney cancer cells: distinct modulations in the expression patterns of apoptosis-related microRNAs and BCL2 family genes.
Tumour Biol. 2015; 36(5):3197-207 [PubMed] Related Publications
Bladder and renal cancer are two representative cases of tumors that respond differentially to gemcitabine. Previous studies have shown that gemcitabine can trigger apoptosis in various cancer cells. Herein, we sought to investigate the impact of gemcitabine on the expression levels of the BCL2 family members BCL2, BAX, and BCL2L12 and the apoptosis-related microRNAs miR-182, miR-96, miR-145, and miR-16 in the human bladder and kidney cancer cell lines T24 and Caki-1, respectively. Cancer cells' viability as well as the IC50 doses of gemcitabine were estimated by the MTT assay, while the detection of cleaved PARP via Western blotting was used as an indicator of apoptosis. Furthermore, T24 and Caki-1 cells' ability to recover from treatment was also monitored. Two different highly sensitive quantitative real-time RT-PCR methodologies were developed in order to assess the expression levels of BCL2 family genes and microRNAs. Exposure of cancer cells to gemcitabine produced the IC50 values of 30 and 3 nM for Caki-1 and T24 cells, correspondingly, while cleaved PARP was detected only in Caki-1 cells. T24 cells demonstrated the ability to recover from gemcitabine treatment, whereas Caki-1 cells' recovery capability was dependent on the initial time of exposure. BCL2 and BAX were significantly modulated in treated Caki-1 cells. Instead, T24 cells exhibited alterations only in the latter, as well as in all studied microRNAs. Therefore, according to our data, bladder and renal cancer cells' response to gemcitabine is accompanied by distinct alterations in the expression levels of their apoptosis-related genes and microRNAs.

Papadopoulos EI, Yousef GM, Scorilas A
Cytotoxic activity of sunitinib and everolimus in Caki-1 renal cancer cells is accompanied by modulations in the expression of apoptosis-related microRNA clusters and BCL2 family genes.
Biomed Pharmacother. 2015; 70:33-40 [PubMed] Related Publications
Sunitinib and everolimus are two of the antineoplastic agents indicated for the management of metastatic renal cancer. Although both of the above compounds were primarily designed as antiangiogenic factors, preclinical studies claim that these drugs can also trigger apoptosis. Herein, we sought to evaluate the cytotoxic activity of sunitinib and everolimus against renal cancer cells Caki-1 and moreover to assess their impact on the expression levels of three BCL2 family members and three apoptosis-related microRNA clusters upon incubation with the drugs or following recovery from treatment. The cytotoxic effect of sunitinib and everolimus on Caki-1 cells' viability was estimated by the MTT assay, while cleaved PARP, assayed via Western Blotting, served as a marker of programmed cell death. As for the expression levels of the BCL2 family members BCL2, BAX and BCL2L12 and those of the mature microRNAs of the miR-183/96/182, miR-143/145, and miR-15a/16 clusters, they were quantified via real-time PCR. Our results showed that both agents induced a time- and dose-dependent decrease in cell viability and promoted cleavage of PARP. In parallel, significant modulations were observed in the expression levels of miR-145, miR-15a, and miR-16 in case of sunitinib, whereas BCL2, BAX, miR-145 and miR-15a expression was strongly affected by everolimus. Overall, our data support the notion that sunitinib and everolimus are able to directly induce cell death in renal cancer cells and simultaneously affect the expression levels of their apoptosis-related microRNAs and BCL2 family members upon this process.

Tzovaras A, Kladi-Skandali A, Michaelidou K, et al.
BCL2L12: a promising molecular prognostic biomarker in breast cancer.
Clin Biochem. 2014; 47(18):257-62 [PubMed] Related Publications
OBJECTIVES: BCL2-like 12 (BCL2L12) is a new member of the BCL2 gene family that was discovered and cloned by members of our group and found to be expressed in the mammary gland. Many genes of the BCL2 family were found to be implicated in breast carcinogenesis and to serve as possible prognostic markers. The aim of the present study was the quantification of BCL2L12 mRNA expression in order to assess its value as a prognostic tissue biomarker in breast cancer (BC).
DESIGN AND METHODS: BCL2L12 mRNA levels were determined in a statistically significant sample size of cancerous (N=108) and adjacent non-cancerous (N=71) breast tissues using a highly sensitive quantitative real-time polymerase chain reaction (qRT-PCR) method. Relative quantification analysis was conducted using the comparative C(T) (2(-ΔΔC)(T)) method, whereas the association between BCL2L12 expression and clinopathological data, disease-free survival (DFS) and overall survival (OS) were estimated by statistical analysis.
RESULTS: BCL2L12 mRNA expression was decreased in malignant samples compared to the histologically normal counterparts (p=0.012). Significant relationships between BCL2L12 expression and TNM stages (p=0.009), metastatic potential (p=0.012), tumor size (p=0.04) and age (p=0.024) were observed. Moreover, Kaplan-Meier and Cox univariate analyses indicated that BCL2L12 expression is associated with longer DFS, whereas multivariate analysis pointed out the independent favorable prognostic value of BCL2L12.
CONCLUSIONS: According to our results, BCL2L12 mRNA expression is a favorable prognostic marker of DFS for BC patients, suggesting its possible application as a novel prognostic indicator of this malignancy.

Gartner JJ, Parker SC, Prickett TD, et al.
Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma.
Proc Natl Acad Sci U S A. 2013; 110(33):13481-6 [PubMed] Free Access to Full Article Related Publications
Synonymous mutations, which do not alter the protein sequence, have been shown to affect protein function [Sauna ZE, Kimchi-Sarfaty C (2011) Nat Rev Genet 12(10):683-691]. However, synonymous mutations are rarely investigated in the cancer genomics field. We used whole-genome and -exome sequencing to identify somatic mutations in 29 melanoma samples. Validation of one synonymous somatic mutation in BCL2L12 in 285 samples identified 12 cases that harbored the recurrent F17F mutation. This mutation led to increased BCL2L12 mRNA and protein levels because of differential targeting of WT and mutant BCL2L12 by hsa-miR-671-5p. Protein made from mutant BCL2L12 transcript bound p53, inhibited UV-induced apoptosis more efficiently than WT BCL2L12, and reduced endogenous p53 target gene transcription. This report shows selection of a recurrent somatic synonymous mutation in cancer. Our data indicate that silent alterations have a role to play in human cancer, emphasizing the importance of their investigation in future cancer genome studies.

Florou D, Patsis C, Ardavanis A, Scorilas A
Effect of doxorubicin, oxaliplatin, and methotrexate administration on the transcriptional activity of BCL-2 family gene members in stomach cancer cells.
Cancer Biol Ther. 2013; 14(7):587-96 [PubMed] Free Access to Full Article Related Publications
Defective apoptosis comprises the main reason for tumor aggressiveness and chemotherapy tolerance in solid neoplasias. Among the BCL-2 family members, whose mRNA or protein expression varies considerably in different human malignancies, BCL2L12 is the one for which we have recently shown its propitious prognostic value in gastric cancer. The purpose of the current work was to investigate the expression behavior of BCL2L12, BAX, and BCL-2 in human stomach adenocarcinoma cells following their exposure to anti-tumor substances. The 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide and trypan blue methods assessed the impact of doxorubicin, oxaliplatin and methotrexate on AGS cells' viability and growth. Following isolation from cells, total RNA was reverse-transcribed to cDNA. Quantification of target genes' expression was performed with real-time PCR using SYBR Green detection system. The relative changes in their mRNA levels between drug-exposed and untreated cells were calculated with the comparative Ct method (2(-ddCt)). All three drugs, as a result of their administration to AGS cancer cells for particular time intervals, provoked substantial fluctuations in the transcriptional levels of the apoptosis-related genes studied. While BAX was principally upregulated, striking similar were the notable changes regarding BCL-2 and BCL2L12 expression in our cellular system. Our findings indicate the growth suppressive effects of doxorubicin, oxaliplatin and methotrexate treatment on stomach carcinoma cells and the implication of BCL2L12, BAX, and BCL-2 expression profiles in the molecular signaling pathways triggered by chemotherapy.

Foutadakis S, Avgeris M, Tokas T, et al.
Increased BCL2L12 expression predicts the short-term relapse of patients with TaT1 bladder cancer following transurethral resection of bladder tumors.
Urol Oncol. 2014; 32(1):39.e29-36 [PubMed] Related Publications
OBJECTIVES: More than half of the diagnosed patients with bladder cancer (BCa) recur at least once following their initial treatment. Thus, patients' monitoring and prognosis is of utmost importance. However, the need for intensive surveillance of BCa significantly burdens patients' health-related quality of life. The aim of the present study is the expression analysis of BCL2L12, a recently identified member of the BCL2 apoptosis-related gene family, in BCa and the evaluation of BCL2L12 prognostic significance for the survival outcome of the patients.
METHODS AND MATERIALS: Our study included 115 patients with BCa, and tissue specimens were obtained from the tumor area as well as from adjacent normal bladder wall. BCL2L12 expression was determined using quantitative real-time polymerase chain reaction assay, and was further correlated with patients' clinicopathological features and follow-up survival data.
RESULTS: Up-regulated BCL2L12 expression levels were detected in malignant bladder specimens compared with normal ones. The higher BCL2L12 expression was further associated with shorter disease-free survival of the patients with BCa. Focusing on patients with TaT1 non-muscle invasive BCa, BCL2L12 expression levels were correlated with higher recurrence rate at the first follow-up cystoscopy and were unveiled to be an independent unfavorable predictor of patients' short-term recurrence following transurethral resection. Finally, BCL2L12 expression levels were also associated with poor disease-free survival of the high-grade TaT1 patients.
CONCLUSIONS: Our data highlight the unfavorable prognostic value of BCL2L12 for patients with BCa and support its potential clinical use for the assessment of TaT1 patients' recurrence risk.

Kontos CK, Fendri A, Khabir A, et al.
Quantitative expression analysis and prognostic significance of the BCL2-associated X gene in nasopharyngeal carcinoma: a retrospective cohort study.
BMC Cancer. 2013; 13:293 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Nasopharyngeal carcinoma (NPC) is a highly metastatic epithelial malignancy showing high prevalence in Southeast Asia and North Africa. The BCL2-associated X (BAX) gene encodes the most important pro-apoptotic member of the BCL2 family. We have recently shown that BCL2 and BCL2L12, two other members of the same apoptosis-related family, possess significant prognostic value in NPC. The objective of the current study was to analyze BAX mRNA expression in nasopharyngeal biopsies of NPC patients, and to assess its prognostic potential in this disease.
METHODS: Total RNA was isolated from 88 malignant and 9 hyperplastic nasopharyngeal biopsies, resected from Tunisian patients. After cDNA synthesis by reverse transcription of polyadenylated RNA, BAX mRNA expression was analyzed using a highly sensitive quantitative real-time polymerase chain reaction (qRT-PCR) method.
RESULTS: Lower BAX mRNA levels were detected in NPC biopsies than in hyperplastic nasopharyngeal samples. BAX mRNA expression status was associated with low tumor extent, negative regional lymph node status, and absence of distant metastases. Kaplan-Meier survival analysis demonstrated that patients with BAX mRNA-positive NPC have significantly longer disease-free survival (DFS) and overall survival (OS). In accordance with these findings, Cox regression analysis revealed that BAX mRNA expression can be considered as a favorable prognostic indicator of DFS and OS in NPC, independent of their gender, age, tumor histology, tumor extent, and nodal status. Furthermore, NPC patients without distant metastases are less likely to relapse when their primary tumor is BAX mRNA-positive, compared to metastasis-free patients with a BAX-negative nasopharyngeal malignancy.
CONCLUSION: This is the first study examining the potential clinical utility of BAX as a prognostic tumor biomarker in NPC. We provide evidence that BAX mRNA expression can be considered as an independent favorable prognostic indicator of DFS and OS in NPC.

Taghavi MS, Akbarzadeh A, Mahdian R, et al.
Cisplatin downregulates BCL2L12, a novel apoptosis-related gene, in glioblastoma cells.
In Vitro Cell Dev Biol Anim. 2013; 49(6):465-72 [PubMed] Related Publications
Glioblastoma progression is mainly characterized by intense apoptosis resistance and marked necrosis. Over-expression of BCL2L12, a novel member of Bcl-2 family has been shown in primary glioblastoma. BCL2L12 blocks effective caspase-3/7 maturation and inhibits p53 tumor suppressor, deriving resistance toward apoptosis and inducing extensive cell necrosis. Cisplatin is a major chemotherapeutic agent which has a broad range of anti-neoplastic activities including apoptosis induction. To investigate the effect of cisplatin on the expression of BCL2L12 in glioblastoma cells, two glioblastoma cell lines were treated with different concentrations of cisplatin for 48 h. The cell viability and IC50 was determined using MTT assay. Then, the two glioblastoma cell lines were treated with 48 h IC50 concentration of cisplatin for 24, 48, and 72 h. Apoptosis induction was analyzed by fluorescence microscopy and flow cytometry. Gene expression study was performed on BCL2L12 and TBP as target and internal control genes, respectively. The quantitative real-time polymerase chain reaction results showed that BCL2L12 gene expression was significantly (p = 0.001) downregulated in the presence of cisplatin. In conclusion, cisplatin treatment induced a time-dependent apoptosis in glioblastoma cells, at least partially via downregulation of BCL2L12 gene expression.

Karan-Djurasevic T, Palibrk V, Zukic B, et al.
Expression of Bcl2L12 in chronic lymphocytic leukemia patients: association with clinical and molecular prognostic markers.
Med Oncol. 2013; 30(1):405 [PubMed] Related Publications
Dysregulation of apoptosis is a distinctive feature of chronic lymphocytic leukemia (CLL), although a unique mechanism underlying apoptosis resistance of CLL B lymphocytes has not been identified yet. Aberrant expression as well as genetic and epigenetic alterations of numerous genes involved in different pathways of apoptosis regulation has been described in CLL. Here, we report the expression analysis of Bcl2L12 (Bcl2-like 12), a novel apoptotic gene belonging to Bcl2 family, in 58 Serbian CLL patients. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) analysis revealed a significant overexpression of Bcl2L12 mRNA in CLL samples compared to non-leukemic samples, implying its role in the pathogenesis of the disease. Receiver operating characteristic (ROC) analysis showed that Bcl2L12 expression efficiently discriminates CLL cases from healthy controls. However, relatively homogenous Bcl2L12 mRNA expression among patients did not reflect their clinical characteristics (with the exception of lactate dehydrogenase status and time from diagnosis to treatment) and failed to show association with the most informative prognostic markers, namely the mutational status of rearranged immunoglobulin heavy chain variable region genes, CD38 and lipoprotein lipase gene (LPL) expression.

Geomela PA, Kontos CK, Yiotakis I, Scorilas A
Quantitative expression analysis of the apoptosis-related gene, BCL2L12, in head and neck squamous cell carcinoma.
J Oral Pathol Med. 2013; 42(2):154-61 [PubMed] Related Publications
BACKGROUND: BCL2L12 is a recently identified gene belonging to the BCL2 family, members of which are implicated in head and neck squamous cell carcinoma (HNSCC). We have recently shown that BCL2L12 mRNA expression is an unfavorable prognostic indicator in nasopharyngeal carcinoma (NPC) and that BCL2L12 can be regarded as a novel, useful tissue biomarker for the prediction of NPC patients' short-term relapse. The aim of this study was to analyze the mRNA expression of the novel apoptosis-related gene BCL2L12 in patients with HNSCC.
METHODS: Total RNA was isolated from 53 malignant tumors originating in larynx, pharynx, tongue, buccal mucosa, parotid glands, and nasal cavity, as well as from 34 adjacent non-cancerous tissue specimens, resected from patients with HNSCC. A highly sensitive real-time PCR method for BCL2L12 mRNA quantification in head and neck tissues was developed using the SYBR(®) Green chemistry. After preparing cDNA by reverse transcription, relative quantification was performed using the comparative C(T) () method.
RESULTS: BCL2L12 mRNA levels were lower in laryngeal tumors of advanced tumor, node, metastasis (TNM) stage or bigger size and in well-differentiated malignant tongue neoplasms, compared with early-stage laryngeal tumors or poorly differentiated tongue tumors. Interestingly, the BCL2L12 expression showed significant discriminatory value, distinguishing efficiently patients with tongue squamous cell carcinoma (SCC) from non-cancerous population.
CONCLUSIONS: This is the first study examining the BCL2L12 mRNA expression in HNSCC. Our results suggest that BCL2L12 mRNA expression may serve as a potential prognostic biomarker in tongue and/or larynx SCC, which principally constitute the great majority of HNSCC cases worldwide.

Thomadaki H, Floros KV, Pavlovic S, et al.
Overexpression of the novel member of the BCL2 gene family, BCL2L12, is associated with the disease outcome in patients with acute myeloid leukemia.
Clin Biochem. 2012; 45(16-17):1362-7 [PubMed] Related Publications
OBJECTIVES: BCL2L12 is a recently discovered and cloned gene from members of our research team. It is a novel member of the BCL2 gene family, members of which are implicated in different hematological malignancies. In the present study, we investigated and studied the expression profile of BCL2L12 in acute myeloid leukemia (AML).
DESIGN AND METHODS: Total RNA was isolated from peripheral blood of 67 AML patients and healthy donors. The expression profile of BCL2L12 was studied using real-time PCR methodology (SYBR Green chemistry). We also evaluated the association of the BCL2L12 mRNA expression level with clinical and pathological disease parameters, as well with disease-free survival (DFS) and overall survival (OS), using the chi-square (χ(2)) test or the Fisher's exact test, where appropriate.
RESULTS: Leukemia patients expressing high level of BCL2L12 were 3 times more likely to relapse (p=0.004) or die (p=0.007) than patients with low level of BCL2L12 expression. Additionally, statistically significant relationships were revealed between BCL2L12 expression level and CD117 expression, the presence of splenomegaly and chemotherapy response.
CONCLUSIONS: Our results suggest that BCL2L12 can be considered as a new independent prognostic and chemotherapy response marker in AML.

Kontos CK, Scorilas A
Molecular cloning of novel alternatively spliced variants of BCL2L12, a new member of the BCL2 gene family, and their expression analysis in cancer cells.
Gene. 2012; 505(1):153-66 [PubMed] Related Publications
In the past, we identified and cloned the BCL2-like 12 (BCL2L12) gene, a novel member of the BCL2 family, which is implicated in various malignancies. The classical BCL2L12 protein isoform contains a highly conserved BH2 domain, a BH3-like motif, and a proline-rich region, and is involved in apoptosis. Most members of this apoptosis-related family are subjected to alternative splicing, thus generating multiple protein isoforms with distinct properties, and sometimes even with opposite function (pro- vs. anti-apoptotic). In the current study, we report the identification, molecular cloning, and expression pattern of novel splice variants of the human BCL2L12 gene in cancer cell lines. EST clones displaying high sequence identity (≥90%) with the classical BCL2L12 transcript were aligned, in order to identify those containing at least one novel splice junction. EST database mining led to the identification of three previously unknown splice variants of this apoptotic gene. In our effort to experimentally validate these novel transcripts, we also cloned seven more, previously unidentified, BCL2L12 alternatively spliced variants. Expression analysis of all BCL2L12 splice variants in human cancer cell lines and embryonic kidney cells revealed remarkable differences between their BCL2L12 expression profiles. Interestingly, 7 out of 10 novel splice variants of BCL2L12 are predicted to encode new protein isoforms, some of which are BH3-only proteins, in contrast to the classical BCL2L12 isoform, which also contains a functional BH2 domain. The remaining three novel splice variants of BCL2L12 are nonsense-mediated mRNA decay (NMD) candidates.

Korbakis D, Scorilas A
Quantitative expression analysis of the apoptosis-related genes BCL2, BAX and BCL2L12 in gastric adenocarcinoma cells following treatment with the anticancer drugs cisplatin, etoposide and taxol.
Tumour Biol. 2012; 33(3):865-75 [PubMed] Related Publications
The BCL2 family of proteins includes apoptosis-related molecules involved in normal physiology, as well as cancer pathology. Members of our team have discovered and cloned the novel gene BCL2L12, which codes for a protein member of the BCL2 family. The BCL2L12 expression has been studied extensively in various types of cancer and its important clinical value has been underlined. The main objective of this study is the relative quantification of the mRNA expression of the apoptosis-related genes BCL2, BAX and BCL2L12 in gastric cancer cells, following treatment with anticancer drugs. Gastric adenocarcinoma cells AGS were treated with various concentrations of the chemical substances cisplatin, etoposide and taxol for three time periods. Cell viability was examined by using the MTT assay. Total RNA was extracted and reverse transcribed into cDNA. A highly sensitive, quantitative real-time PCR method was developed based on the SYBR Green chemistry, for the proper mRNA quantification. GAPDH was used as a housekeeping gene. Relative quantification analysis was performed by using the comparative C(T) method ([Formula: see text]). Treatment of AGS cells with 10 μM cisplatin, 0.5 μM etoposide and 10 nM taxol affected the BCL2, BAX and BCL2L12 mRNA levels, compared to the untreated cells. Cisplatin and etoposide induced a major down-regulation in the BCL2 mRNA levels after 72 h of treatment, while the BAX mRNA levels were slightly up-regulated. Moreover, taxol had an up-regulating effect on both BCL2 and BAX transcript levels after 48 h of incubation. Chemotherapy had a much smaller effect on the BCL2L12 expression levels, eventually characterised by a small down-regulation.

Papageorgiou SG, Kontos CK, Pappa V, et al.
The novel member of the BCL2 gene family, BCL2L12, is substantially elevated in chronic lymphocytic leukemia patients, supporting its value as a significant biomarker.
Oncologist. 2011; 16(9):1280-91 [PubMed] Free Access to Full Article Related Publications
BCL2L12 is a recently identified gene belonging to the BCL2 family, members of which are implicated in hematologic malignancies, including chronic lymphocytic leukemia (CLL). The aim of this study was to analyze the mRNA expression of the novel apoptosis-related gene BCL2L12 in patients with CLL and to examine its prognostic and predictive value and potential clinical application as a novel molecular biomarker for CLL. For this purpose, total RNA was isolated from peripheral blood of 65 CLL patients and 23 healthy donors. An ultrasensitive quantitative real-time polymerase chain reaction methodology for BCL2L12 and BCL2 mRNA quantification was developed using SYBR Green chemistry. After preparing cDNA by reverse transcription, relative quantification analysis was performed using the comparative C(T) (2(-ΔΔCT)) method. Furthermore, analysis of IGHV mutational status, CD38 expression, and detection of early apoptosis by double staining with Annexin V-FITC and propidium iodide were performed. According to our findings, BCL2L12 mRNA expression is significantly higher in CLL patients than in healthy donors. Receiver operating characteristic analysis demonstrated that BCL2L12 expression had significant discriminatory value, distinguishing very efficiently CLL patients from the non-leukemic population. Moreover, BCL2L12 expression predicts the presence of CLL, as demonstrated by both univariate and multivariate logistic regression analyses. Finally, high BCL2L12 mRNA levels are associated with advanced clinical stage and predict shorter overall survival in CLL patients.

Stegh AH, DePinho RA
Beyond effector caspase inhibition: Bcl2L12 neutralizes p53 signaling in glioblastoma.
Cell Cycle. 2011; 10(1):33-8 [PubMed] Free Access to Full Article Related Publications
Malignant gliomas are the most common and lethal primary central nervous system cancer. Glioblastoma mutliforme (GBM), the most aggressive of these neoplasms, are generally lethal within 2 years of diagnosis due in part to the intense apoptosis resistance of its cancer cells, hence poor therapeutic response to conventional and targeted therapies.  Twenty years of research has uncovered key genetic events involved in disease initiation and progression, foremost the Tp53 tumor suppressor that is mutated or deleted in 35% of GBM. The prime importance of p53 signaling for gliomapathogenesis is further evidenced by epistatic genetic events targeting additional pathway components including deletion of p14 (Arf) (CDKN2A) and amplification of the p53-degrading ubiquitin ligases MDM2 and MDM4.  Recent studies have identified and validated Bcl2-Like 12 (Bcl2L12) as a potent glioma oncoprotein with multiple strategic points in apoptosis regulatory networks, i.e. effector caspases and the p53 tumor suppressor. Bcl2L12 resides in both the cytoplasm and nucleus.  In the cytoplasm, Bcl2L12 functions to inhibit caspases 3 and 7, in the nucleus, Bcl2L12 forms a complex with p53, modestly reduces p53 protein stability and prevents its binding to selected target gene promoter (e.g. p21, DR5, Noxa and PUMA), thereby inhibiting p53-directed transcriptomic changes upon DNA damage. Proteomic and multidimensional oncogenomic analyses confirmed a Bcl2L12-p53 signaling axis in GBM, as Bcl2L12 exhibited predominant genomic amplification, elevated mRNA and protein levels in GBM tumors with uncompromised p53 function. On the cell biological level, Bcl2L12 exerts robust inhibition of p53-dependent senescence and apoptosis processes in glioma cells. These multi-leveled studies establish Bcl2L12 as an important oncoprotein acting at the intersection of nuclear p53 and cytoplasmic caspase signaling and point to pharmacological disruption of the Bcl2L12:p53 complex as a promising novel therapeutic strategy for the enhanced treatment of GBM.

Fendri A, Kontos CK, Khabir A, et al.
BCL2L12 is a novel biomarker for the prediction of short-term relapse in nasopharyngeal carcinoma.
Mol Med. 2011 Mar-Apr; 17(3-4):163-71 [PubMed] Free Access to Full Article Related Publications
BCL2-like 12 (BCL2L12 ) is a new member of the apoptosis-related BCL2 gene family, members of which are implicated in various malignancies. Nasopharyngeal carcinoma is a highly metastatic, malignant epithelial tumor, with a high prevalence in Southeast Asia and North Africa. The purpose of the current study was to quantify and investigate the expression levels of the BCL2L12 gene in nasopharyngeal carcinoma biopsies and to assess its prognostic value. Total RNA was isolated from 89 malignant and hyperplastic nasopharyngeal biopsies from Tunisian patients. After testing the quality of the extracted RNA, cDNA was prepared by reverse transcription. A highly sensitive real-time polymerase chain reaction (PCR) method for BCL2L12 mRNA quantification was developed using SYBR Green chemistry. GAPDH served as a reference gene. Relative quantification analysis was performed using the comparative C(T) (2(-ΔΔCT)) method. Higher BCL2L12 mRNA levels were detected in undifferentiated carcinomas of the nasopharynx, rather than in nonkeratinizing nasopharyngeal tumors (P = 0.045). BCL2L12 expression status was also found to be positively associated with the presence of distant metastases (P = 0.014). Kaplan-Meier survival analysis demonstrated that patients with BCL2L12-positive nasopharyngeal tumors have significantly shorter disease-free survival (P = 0.020). Cox regression analysis showed BCL2L12 expression to be an unfavorable and independent prognostic indicator of short-term relapse in nasopharyngeal carcinoma (P = 0.042). Our results suggest that mRNA expression of BCL2L12 may constitute a novel biomarker for the prediction of short-term relapse in nasopharyngeal carcinoma.

Resende C, Ristimäki A, Machado JC
Genetic and epigenetic alteration in gastric carcinogenesis.
Helicobacter. 2010; 15 Suppl 1:34-9 [PubMed] Related Publications
Gastric cancer (GC) is an important cause of morbidity and mortality worldwide. In addition to environmental factors, genetic factors also play an important role in GC etiology, as demonstrated by the fact that only a small proportion of individuals exposed to the known environmental risk factors develop GC. Molecular studies have provided evidence that GC arises not only from the combined effects of environmental factors and susceptible genetic variants but also from the accumulation of genetic and epigenetic alterations that play crucial roles in the process of cellular immortalization and tumorigenesis. This review is intended to focus on the recently described basic aspects that play key roles in the process of gastric carcinogenesis. Genetic variation in the genes DNMT3A, PSCA, VEGF, and XRCC1 has been reported to modify the risk of developing gastric carcinoma. Several genes have been newly associated with gastric carcinogenesis, both through oncogenic activation (MYC, SEMA5A, BCL2L12, RBP2 and BUBR1) and tumor suppressor gene inactivation mechanisms (KLF6, RELN, PTCH1A, CLDN11, and SFRP5). At the level of gastric carcinoma treatment, the HER-2 tyrosine kinase receptor has been demonstrated to be a molecular target of therapy.

Stegh AH, Brennan C, Mahoney JA, et al.
Glioma oncoprotein Bcl2L12 inhibits the p53 tumor suppressor.
Genes Dev. 2010; 24(19):2194-204 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) is a lethal brain tumor characterized by intense apoptosis resistance and extensive necrosis. Bcl2L12 (for Bcl2-like 12) is a cytoplasmic and nuclear protein that is overexpressed in primary GBM and functions to inhibit post-mitochondrial apoptosis signaling. Here, we show that nuclear Bcl2L12 physically and functionally interacts with the p53 tumor suppressor, as evidenced by the capacity of Bcl2L12 to (1) enable bypass of replicative senescence without concomitant loss of p53 or p19 (Arf), (2) inhibit p53-dependent DNA damage-induced apoptosis, (3) impede the capacity of p53 to bind some of its target gene promoters, and (4) attenuate endogenous p53-directed transcriptomic changes following genotoxic stress. Correspondingly, The Cancer Genome Atlas profile and tissue protein analyses of human GBM specimens show significantly lower Bcl2L12 expression in the setting of genetic p53 pathway inactivation. Thus, Bcl2L12 is a multifunctional protein that contributes to intense therapeutic resistance of GBM through its ability to operate on two key nodes of cytoplasmic and nuclear signaling cascades.

Florou D, Papadopoulos IN, Scorilas A
Molecular analysis and prognostic impact of the novel apoptotic gene BCL2L12 in gastric cancer.
Biochem Biophys Res Commun. 2010; 391(1):214-8 [PubMed] Related Publications
Stomach cancer comprises a malignancy with feeble prognosis. In gastric carcinogenesis, molecular alterations in the apoptosis-related genes have been described. In this study, the expression of BCL2-like-12 (BCL2L12) gene, discovered and cloned by members of our group, was investigated in a statistically significant sample size of cancerous and non-cancerous stomach tissues and gastric cancer cells with quantitative real-time PCR methodology. BCL2L12 transcript was indicated in cancer gastric tissues to range from 29 to 53200 mRNA copies BCL2L12/10(6) mRNA copies GAPDH. Significant associations of BCL2L12 with gastric tumors of the early stages (I/II) (p=0.044) and of intestinal histotype (p=0.034) was substantiated. Both univariate and multivariate analyses disclosed, respectively, BCL2L12 relationship with disease-free (p=0.006 and p=0.025) and overall patients' survival (p=0.007 and p=0.022). Our results open new horizons for the possible application of BCL2L12 as a novel prognostic indicator of gastric cancer.

Drucker KL, Kitange GJ, Kollmeyer TM, et al.
Characterization and gene expression profiling in glioma cell lines with deletion of chromosome 19 before and after microcell-mediated restoration of normal human chromosome 19.
Genes Chromosomes Cancer. 2009; 48(10):854-64 [PubMed] Free Access to Full Article Related Publications
Nearly 10% of human gliomas are oligodendrogliomas. Deletion of chromosome arm 19q, often in conjunction with deletion of 1p, has been observed in 65-80% of these tumors. This has suggested the presence of a tumor suppressor gene located on the 19q arm. Chromosome 19 deletion is also of interest due to the better prognosis of patients with deletion, including longer survival and better response to chemotherapy, compared with patients without deletion. Two glioma cell lines with deletion of 19q were used for chromosome 19 microcell-mediated transfer, to assess the effect of replacing the deleted segment. Complementation with chromosome 19 significantly reduced the growth rate of the hybrid cells compared with the parental cell lines. Affymetrix U133 Plus 2.0 Gene Chip analysis was performed to measure and compare the expression of the chromosome 19 genes in the chromosome 19 hybrid cell lines to the parental cell line. Probes were considered significantly different when a P value <0.01 was seen in all of the cell line comparisons. Of 345 probes within the commonly deleted 19q region, seven genes (APOE, RCN3, FLJ10781, SAE1, STRN4, CCDC8, and BCL2L12) were identified as potential candidate genes. RT-PCR analysis of primary tumor specimens showed that several genes had significant differences when stratified by tumor morphology or deletion status. This suggests that one or more of these candidates may play a role in glioma formation or progression.

Korbakis D, Scorilas A
Treatment of gastric cancer cells with 5-fluorouracil/leucovorin and irinotecan induces distinct alterations in the mRNA expression of the apoptosis-related genes, including the novel gene BCL2L12.
Tumour Biol. 2009; 30(2):100-7 [PubMed] Related Publications
The BCL2 (bcl-2)family of genes is highly involved in the apoptotic mechanisms. We have recently discovered and cloned a novel member of the same family, BCL2L12. The aim of this study was to investigate the modulations in the BAX, BCL2 and BCL2L12 mRNA levels in gastric cancer cells, after their treatment with the anticancer drugs 5-fluorouracil and irinotecan as well as the antioxidant substance leucovorin. AGS gastric cancer cells were examined for their sensitivity to antineoplastic drugs and/or antioxidants using the MTT assay. Total RNA was extracted and reverse transcribed into cDNA. A highly sensitive quantitative real-time PCR method for the mRNA quantification was developed using the SYBR Green chemistry. GAPDH was used as a housekeeping gene. Relative quantification analysis was performed using the comparative threshold cycle method. Treatment of AGS cells with 5-fluorouracil (5 microM), leucovorin (10 microM), a combination of the latter and, eventually, irinotecan (1 microM) for 3 time periods (24, 48 and 72 h), resulted in significant modulations of the BCL2, BAX and BCL2L12 mRNA levels compared with the untreated cells. Our experimental data demonstrate that the molecular profile mainly of BCL2 and BCL2L12 genes may serve as a new potential molecular biomarker predicting treatment response in gastric cancer cells.

Zhuo Z, Zhang L, Mu Q, et al.
The effect of combination treatment with docosahexaenoic acid and 5-fluorouracil on the mRNA expression of apoptosis-related genes, including the novel gene BCL2L12, in gastric cancer cells.
In Vitro Cell Dev Biol Anim. 2009 Jan-Feb; 45(1-2):69-74 [PubMed] Related Publications
Docosahexaenoic acid (DHA) plays an important role in suppressing the growth of cancer. In this paper, the synergetic anticancer effect of combination DHA with 5-fluorouracil (5-FU) was investigated in gastric carcinoma cells. We found that DHA inhibited the growth of cultured SGC7901 cells at different concentrations in a dose- and time-dependent manner. Furthermore, the growth-inhibition activities of increasing concentration of 5-FU were markedly enhanced when different doses of 5-FU were administered in the combination with dose as low as 40 microg/ml of DHA. The early phase of apoptosis was increased in DHA- and 5-FU-treated cells. In the case of apoptotic genes expression in the combination-treated cells, BAX mRNA expression increased, whereas FAS, BCL-2, BCL2L12, and CASPASE-9 mRNA expression decreased. These results suggest that DHA strongly enhances the anticancer effect of 5-FU. Moreover, the application of both compounds on gastric cancer cells provides a new potential approach for cancer therapy.

Hong Y, Yang J, Wu W, et al.
Knockdown of BCL2L12 leads to cisplatin resistance in MDA-MB-231 breast cancer cells.
Biochim Biophys Acta. 2008; 1782(11):649-57 [PubMed] Related Publications
BCL2L12, a newly identified member of Bcl-2 family, contains a BH2 domain and a putative BH3 domain. It was found to be highly expressed in normal breast tissues, and was associated with favorable prognosis in breast cancer patients. Here, we reported that the mRNA levels of BCL2L12 and its transcript variant BCL2L12A could be upregulated upon cisplatin treatment in MDA-MB-231 breast cancer cells. Knockdown of BCL2L12 and BCL2L12A dramatically inhibited cisplatin-induced apoptosis. In contrast, ectopic expressions of each of the proteins promoted cisplatin-induced apoptosis. These results indicated that decreased expressions or loss of BCL2L12 and BCL2L12A may contribute to the cisplatin resistance in breast cancer patients. Furthermore, we found that cisplatin-induced downregulation of beta-catenin was partially suppressed in BCL2L12- and BCL2L12A-knocked down MDA-MB-231 cells, which indicated that knockdown of these two proteins may stabilize beta-catenin in cisplatin-induced apoptosis. In short, we proposed that BCL2L12 and BCL2L12A may play an important role in cisplatin-induced apoptosis in MDA-MB-231 breast cancer cells.

Kontos CK, Papadopoulos IN, Scorilas A
Quantitative expression analysis and prognostic significance of the novel apoptosis-related gene BCL2L12 in colon cancer.
Biol Chem. 2008; 389(12):1467-75 [PubMed] Related Publications
Apoptosis is a tightly regulated process that plays a critical role in many biological events. Members of the BCL2 (Bcl-2) family of apoptosis-related genes have been found to be differentially expressed in various malignancies and have been proposed as prognostic tumor biomarkers. We have recently discovered and cloned a new member of the BCL2 gene family, BCL2L12, expressed in colon tissues. Here we have investigated expression of the BCL2L12 gene in colon cancer tissues and assessed its prognostic value. Total RNA was isolated from 96 specimens of malignant colon tissue. After testing the RNA quality, cDNA was prepared by reverse transcription. A highly sensitive real-time PCR method for BCL2L12 mRNA quantification was developed using SYBR Green chemistry. GAPDH served as a housekeeping gene. Relative quantification analysis was performed using the comparative C(T) method (2(-DeltaDeltaCT)). High BCL2L12 expression levels were found in smaller (< or =5 cm, p=0.027) and well-differentiated tumors (p=0.034), as well as in early-stage tumors (p=0.039). Survival analysis demonstrated that patients with BCL2L12-positive colon tumors have significantly longer disease-free survival and overall survival (p=0.015 and p=0.027, respectively). Our results suggest that BCL2L12 gene expression may represent a potential new biomarker for colon cancer.

Thomadaki H, Scorilas A
Molecular profile of breast versus ovarian cancer cells in response to treatment with the anticancer drugs cisplatin, carboplatin, doxorubicin, etoposide and taxol.
Biol Chem. 2008; 389(11):1427-34 [PubMed] Related Publications
We assessed changes in the apoptosis-related genes BCL2, BAX, BCL2L12, FAS and CASPASE-3 in OVCAR-3 human ovarian cancer cells and BT-20 human breast cancer cells to provide an insight into the molecular mechanisms involved in the response of these cells to treatment with anticancer drugs and to assess their value as potential biomarkers of chemotherapy response in breast and ovarian cancer. Cells were treated with different chemotherapeutic drugs (cisplatin, carboplatin, doxorubicin, etoposide and taxol) and assessed for changes in the expression of apoptosis-related genes at the mRNA level. Total RNA was extracted, reverse-transcribed into cDNA and amplified by PCR using gene-specific primers. GAPDH was used as a housekeeping gene. Cytotoxicity was assessed by MTT assay. Both cancer cell lines responded differentially at the molecular level to the drug treatments. OVCAR-3 cells showed more pronounced sensitivity and changes compared to BT-20 cells at the mRNA level for different apoptosis-related genes, leading to cell and cancer type dependence in conjunction with drug dependence.

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