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Identification and functional analysis of a novel splice variant of AC3-33 in breast cancer.

ABSTRACT: Alternative RNA splicing plays a key role in regulating gene function and influencing protein expression diversity. In the present study, an AC-33 transcript variant (NCBI Reference Sequence: NM_001308229.1), splice variant (sv)AC3-33, was successfully cloned from the MCF-7 breast cancer cell line by reverse transcription PCR using primers based on expressed sequence tags. The aim of the present study was to investigate the structure and function of svAC3-33. svAC3-33 has an open reading frame of 1,825 base pairs, lacks AC3-33 exon 2 and is encoded by 294 amino acids. svAC3-33 is localized within the cytoplasm. The Cell Counting Kit-8 and EdU detection of cell proliferation assays showed that svAC3-33 inhibited MCF-7 cell proliferation. Similarly, svAC3-33 knockdown by RNA interference was shown to have the opposite effect by repressing the cell cycle progression of breast cancer cells. Furthermore, the data indicated that svAC3-33 may upregulate the expression of p21. The present study provides evidence that the increased expression of svAC3-33 may inhibit the activity of the transcription factor AP-1. The luciferase reporter gene assay detected a downregulation of the expression of c-Jun, but not c-Fos, which in turn affected cell proliferation. In conclusion, these results indicated a function for svAC3-33 in inhibiting the cell proliferation of MCF-7 cells by regulating the AP-1 signaling pathway.

SUBMITTER: Yuan L

PROVIDER: S-EPMC6909594 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Identification and functional analysis of a novel splice variant of AC3-33 in breast cancer.

Yuan Lu L Hu Fen F Zhang Yunfeng Y Meng Lijun L An Tianyang T Chen Yajing Y Zhang Xiujun X

Experimental and therapeutic medicine 20191118 1

Alternative RNA splicing plays a key role in regulating gene function and influencing protein expression diversity. In the present study, an AC-33 transcript variant (NCBI Reference Sequence: NM_001308229.1), splice variant (sv)AC3-33, was successfully cloned from the MCF-7 breast cancer cell line by reverse transcription PCR using primers based on expressed sequence tags. The aim of the present study was to investigate the structure and function of svAC3-33. svAC3-33 has an open reading frame o ...[more]

PMID: 31853289

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Project description:Type III interferons (IFNLs) have critical roles in the host's innate immune system, also serving as the first line against pathogenic infections of mucosal surfaces. In mammals, several IFNLs have been reported; however, only limited data on the repertoire of IFNLs in avian species is available. Previous studies showed only one member in chicken (chIFNL3). Herein, we identified a novel chicken IFNL for the first time, termed chIFNL3a, which contains 354 bp, and encodes 118 amino acids. The predicted protein is 57.1% amino acid identity with chIFNL. Genetic, evolutionary, and sequence analyses indicated that the new open reading frame (ORF) groups with type III chicken IFNs represent a novel splice variant. Compared to IFNs from different species, the new ORF is clustered within the type III IFNs group. Further study showed that chIFNL3a could activate a panel of IFN-regulated genes and function mediated by the IFNL receptor, and chIFNL3a markedly inhibited the replication of Newcastle disease virus (NDV) and influenza virus in vitro. These data collectively shed light on the repertoire of IFNs in avian species and provide useful information that further elucidate the interaction of the chIFNLs and viral infection of poultry. IMPORTANCE Interferons (IFNs) are critical soluble factors in the immune system, and are composed of 3 types (I, II, and III) that utilize different receptor complexes (IFN-αR1/IFN-αR2, IFN-γR1/IFN-γR2, and IFN-λR1/IL-10R2, respectively). Herein, we identified IFNL from the genomic sequences of chicken and termed it chIFNL3a, located on chromosome 7 of chicken. Phylogenetically clustered with all known types of chicken IFNs, the finding of this IFN is considered a type III IFN. To further evaluate the biological properties of chIFNL3a, the target protein was prepared by the baculovirus expression system (BES), which could markedly inhibit the replication of NDV and influenza viruses. In this study, we uncovered a new interferon lambda splice variant of chicken, termed chIFNL3a, which could inhibit viral replication in cells. Importantly, these novel findings may extend to other viruses, offering a new direction for therapeutic interventions.

Project description:Purpose: Adjuvant tamoxifen treatment revolutionized the management of estrogen receptor (ER)-positive breast cancers to prevent cancer recurrence; however, drug resistance compromises its clinical efficacy. The mechanisms underlying tamoxifen resistance are not fully understood, and no robust biomarker is available to reliably predict those who will be resistant. Here, we study BQ323636.1, a novel splice variant of the NCOR2 gene, and evaluate its efficacy in predicting tamoxifen resistance in patients with breast cancer.Experimental Design: A monoclonal anti-BQ323636.1 antibody that specifically recognizes the unique epitope of this splice variant was generated for in vitro mechanistic studies and for in vivo analysis by immunohistochemistry on tissue microarrays of two independent cohorts of 358 patients with more than 10 years clinical follow-up data, who had ER-positive primary breast cancer and received adjuvant tamoxifen treatment. An orthotopic mouse model was also used.Results: Overexpression of BQ323636.1 conferred resistance to tamoxifen in both in vitro and in an orthotopic mouse model. Mechanistically, coimmunoprecipitation showed BQ323636.1 could bind to NCOR2 and inhibit the formation of corepressor complex for the suppression of ER signaling. Nuclear BQ3232636.1 overexpression in patients samples was significantly associated with tamoxifen resistance (P = 1.79 × 10-6, sensitivity 52.9%, specificity 72.0%). In tamoxifen-treated patients, nuclear BQ323636.1 overexpression was significantly correlated with cancer metastasis and disease relapse. Nuclear BQ323636.1 was also significantly associated with poorer overall survival (P = 1.13 × 10-4) and disease-specific survival (P = 4.02 × 10-5).Conclusions: These findings demonstrate that BQ323636.1 can be a reliable biomarker to predict tamoxifen resistance in patients with ER-positive breast cancer. Clin Cancer Res; 24(15); 3681-91. ©2018 AACRSee related commentary by Jordan, p. 3480.

Dataset Information

Identification and functional analysis of a novel splice variant of AC3-33 in breast cancer.

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Identification and functional analysis of a novel splice variant of AC3-33 in breast cancer.

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