Distinct molecular subtypes of uterine leiomyosarcoma respond differently to chemotherapy treatment

An, Yang; Wang, Shuzhen; Li, Songlin; Zhang, Lulu; Wang, Dayong; Wang, Haojie; Zhu, Shibai; Zhu, Wan; Li, Yongqiang; Chen, Wenwu; Ji, Shaoping; Guo, Xiangqian

doi:10.1186/s12885-017-3568-y

Cited by 19 publications

(17 citation statements)

References 38 publications

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“…HOXA1, one of the HOXA gene cluster members, has been found to be up-regulated in human malignancies, such as non-small cell lung cancer [ 30 ], oral squamous cell carcinoma [ 31 ], uterine leiomyosarcoma [ 32 ] and breast cancer [ 33 – 35 ], and function as an oncogene. For example, the high expression level of HOXA1 promotes distant metastasis of melanoma [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Over-expressed lncRNA HOTAIRM1 promotes tumor growth and invasion through up-regulating HOXA1 and sequestering G9a/EZH2/Dnmts away from the HOXA1 gene in glioblastoma multiforme

Dong

Cui

et al. 2018

J Exp Clin Cancer Res

136

109

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BackgroundGlioblastoma multiforme (GBM) is the common primary brain tumor classified the most malignant glioma. Long non-coding RNAs (LncRNAs) are important epigenetic regulators with critical roles in cancer initiation and progression. LncRNA HOTAIRM1 transcribes from the antisense strand of HOXA gene cluster which locus in chromosome 7p15.2. Recent studies have shown that HOTAIRM1 is involved in acute myeloid leukemia and colorectal cancer. Here we sought to investigate the role of HOTAIRM1 in GBM and explore its mechanisms of action.MethodsThe expressions of HOTAIRM1 and HOXA1 in GBM tissues and cells were determined by qRT-PCR, and the association between HOTAIRM1, HOXA1 transcription and tumor grade were analyzed. The biological function of HOTAIRM1 in GBM was evaluated both in vitro and in vivo. Chromatin immunoprecipitation (ChIP) assay and quantitative Sequenom MassARRAY methylation analysis were performed to explore whether HOTAIRM1 could regulate histone and DNA modification status of the HOXA1 gene transcription start sites (TSS) and activate its transcription. ChIP and RNA-ChIP were further performed to determine the molecular mechanism of HOTAIRM1 in epigenetic regulation of the HOXA1 gene.ResultsHOTAIRM1 was abnormally up-regulated in GBM tissues and cells, and this up-regulation was correlated with grade malignancy in glioma patients. HOTAIRM1 silencing caused tumor suppressive effects via inhibiting cell proliferation, migration and invasion, and inducing cell apoptosis. In vivo experiments showed knockdown of HOTAIRM1 lessened the tumor growth. Additionally, HOTAIRM1 action as regulating the expression of the HOXA1 gene. HOXA1, as an oncogene, it’s expression levels were markedly elevated in GBM tissues and cell lines. Mechanistically, HOTAIRM1 mediated demethylation of histone H3K9 and H3K27 and reduced DNA methylation levels by sequester epigenetic modifiers G9a and EZH2, which are H3K9me2 and H3K27me3 specific histone methyltransferases, and DNA methyltransferases (DnmTs) away from the TSS of HOXA1 gene.ConclusionsWe investigated the potential role of HOTAIRM1 to promote GBM cell proliferation, migration, invasion and inhibit cell apoptosis by epigenetic regulation of HOXA1 gene that can be targeted simultaneously to effectively treat GBM, thus putting forward a promising strategy for GBM treatment. Meanwhile, this finding provides an example of transcriptional control over the chromatin state of gene and may help explain the role of lncRNAs within the HOXA gene cluster.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0941-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Over-expressed lncRNA HOTAIRM1 promotes tumor growth and invasion through up-regulating HOXA1 and sequestering G9a/EZH2/Dnmts away from the HOXA1 gene in glioblastoma multiforme

Dong

Cui

et al. 2018

J Exp Clin Cancer Res

136

109

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“…STS encompass a variety of pathologic tissue types with limited treatment options available . Indeed, alterations in the HR pathway have previously been noted to be more frequent in uLMS , and this lends credence that uLMS is a distinct subgroup from nonuterine LMS . The frequency of these alterations, as well as their potential targetability with PARP inhibitors, has yet to be confirmed in a large patient cohort.…”

Section: Discussionmentioning

confidence: 99%

BRCA1/2 Functional Loss Defines a Targetable Subset in Leiomyosarcoma

et al. 2018

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Background Soft‐tissue sarcomas (STS) describe a heterogeneous group of mesenchymal tumors with limited treatment options. Targeted therapies exist for BRCA1/2 gene alterations, but their prevalence and role have not been fully described in STS. Here, we present the largest effort to characterize the frequency of homologous recombination (HR) DNA repair pathway alterations in STS subtypes and highlight the unique nature of leiomyosarcoma (LMS). Materials and Methods DNA sequencing data were analyzed for HR pathway alterations for 1,236 patients with STS. DNA sequencing data from an additional 1,312 patients were used to confirm the prevalence of HR pathway alterations in LMS. Four uterine LMS (uLMS) patients with functional BRCA2 loss were evaluated for response to poly (ADP‐ribose) polymerase (PARP) inhibition. Results In an unselected STS study population, BRCA2 alterations were identified in 15 (1%) patients, and homozygous BRCA2 loss was detected in 9 (<1%). However, subset analysis revealed that these BRCA2 alterations were concentrated in uLMS as compared with any other STS subtype. Notably, 10% of uLMS tumors had a BRCA2 alteration. We further report that PARP inhibitors had demonstrated durable clinical benefit in four uLMS patients with BRCA2 loss. Conclusion HR pathway alterations are rare in most STS. However, we identify uLMS to be enriched for BRCA2 loss and report the positive outcomes of a series of patients treated with PARP inhibitors. Our data suggest that patients with uLMS should be considered for somatic BRCA2 profiling. Prospective trials are necessary to confirm the efficacy of PARP inhibition in uLMS. Implications for Practice Soft‐tissue sarcomas are a highly morbid, diverse set of tumors with limited treatment options. This study identifies an increased prevalence of functional BRCA1/2 loss in patients with uterine leiomyosarcoma (uLMS). It also presents four patients with uLMS and BRCA2 loss who achieved durable clinical benefit from poly (ADP‐ribose) polymerase inhibition. These data suggest that patients with uLMS in particular should be screened for BRCA1/2 alterations and may benefit from treatment targeted to these alterations.

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“…Molecular heterogeneity has been demonstrated to contribute to the cancer recurrence and metastasis after treatment, and to be even resistant to treatment. Gene expression-based molecular subtyping has been successful in identifying subtypes of a number of tumors (including breast cancer, colon cancer, melanoma, lung cancer, leiomyosarcoma, uterine carcinosarcoma, and uterine leiomyosarcoma), which subsequently led to remarkable benefits in clinical treatments and prognosis [13], [14], [15], [16], [17], [18], [19]. To date, a number of studies have investigated the genomic and molecular signatures of ESCC [2], [4], [11], [20]; however, only few have attempted to stratify ESCC into different molecular subtypes [6], [21].…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Profiling Reveals Distinct Molecular Subtypes of Esophageal Squamous Cell Carcinoma in Asian Populations

Wang

Yan

et al. 2019

Neoplasia

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Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide, particularly in Asian populations, and responds poorly to conventional therapy. Subclassification of ESCCs by molecular analysis is a powerful strategy in extending conventional clinicopathologic classification, improving prognosis and therapy. Here we identified two ESCC molecular subtypes in Chinese population using gene expression profiling data and further validated the molecular subtypes in two other independent Asian populations (Japanese and Vietnamese). Subtype I ESCCs were enriched in pathways including immune response, while genes overexpressed in subtype II ESCCs were mainly involved in ectoderm development, glycolysis process, and cell proliferation. Specifically, we identified potential ESCC subtype-specific diagnostic markers (FOXA1 and EYA2 for subtype I, LAMC2 and KRT14 for subtype II) and further validated them in a fourth Asian cohort. In addition, we propose a few subtype-specific therapeutic targets for ESCC, which may guide future ESCC clinical treatment when further validated.

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Distinct molecular subtypes of uterine leiomyosarcoma respond differently to chemotherapy treatment

Cited by 19 publications

References 38 publications

Over-expressed lncRNA HOTAIRM1 promotes tumor growth and invasion through up-regulating HOXA1 and sequestering G9a/EZH2/Dnmts away from the HOXA1 gene in glioblastoma multiforme

Over-expressed lncRNA HOTAIRM1 promotes tumor growth and invasion through up-regulating HOXA1 and sequestering G9a/EZH2/Dnmts away from the HOXA1 gene in glioblastoma multiforme

BRCA1/2 Functional Loss Defines a Targetable Subset in Leiomyosarcoma

Gene Expression Profiling Reveals Distinct Molecular Subtypes of Esophageal Squamous Cell Carcinoma in Asian Populations

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