Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation

Dou, Zhihui; Zhao, Dapeng; Chen, Xiaohua; Xu, Chong; Jin, Xiaodong; Zhang, Xuetian; Wang, Yupei; Xie, Xiaodong; Li, Qiang; Chen, Di; Zhang, Hong

doi:10.1186/s13046-021-02001-w

Cited by 26 publications

(19 citation statements)

References 188 publications

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“…76,77 BECN1 augmented the formation of autophagosomes through hVps34-Beclin-1 complex, and the process could be disrupted by Bcl-xL. 78 Based on the above results, the autophagy mediated by matrix stiffness may be regulated by Bcl-x protein. Along with the increasing matrix stiffness, the expression of miR-1972 displayed significant upregulation, then promoted the initiation of autophagy through inhibiting the interaction between Bcl-x and BCEN1.…”

Section: Resultsmentioning

confidence: 73%

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Matrix stiffness triggers chemoresistance through elevated autophagy in pancreatic ductal adenocarcinoma

Pan,

Zhu,

Gong

et al. 2023

Biomater. Sci.

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Section: Resultsmentioning

confidence: 73%

Section: Biomaterials Science Papermentioning

confidence: 76%

Matrix stiffness triggers chemoresistance through elevated autophagy in pancreatic ductal adenocarcinoma

Pan,

Zhu,

Gong

et al. 2023

Biomater. Sci.

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“…Notably, isoforms can also play entirely different, or even opposite roles within a given cell; a classic example includes two well-studied BCL-X (BCL2L1) transcripts with opposite functions, where BCL-X L is anti-apoptotic while BCL-X S is pro-apoptotic 6 . Changes in expression ratio between the BCL-X isoforms are implicated in cancer and are being studied as therapeutic targets 12 , demonstrating the importance of understanding individual RNA isoform function rather than treating them as a “single” gene (i.e., a single function).…”

Section: Mainmentioning

confidence: 99%

Using deep long-read RNAseq in Alzheimer’s disease brain to assess medical relevance of RNA isoform diversity

Heberle,

Brandon,

Page

et al. 2023

Preprint

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Due to alternative splicing, human protein-coding genes average over eight RNA isoforms, resulting in nearly four distinct protein coding sequences per gene. Long-read RNAseq (IsoSeq) enables more accurate quantification of isoforms, shedding light on their specific roles. To assess the clinical relevance of measuring RNA isoform expression, we sequenced 12 aged human frontal cortices (6 Alzheimer's disease cases and 6 controls, 50% female) using one Oxford Nanopore PromethION flow cell per sample. Our study uncovered 53 new high-confidence RNA isoforms in clinically relevant genes, including several where the new isoform was one of the most highly expressed for that gene. Specific examples include WDR4 (61%; microcephaly), MYL3 (44%; hypertrophic cardiomyopathy), and MTHFS (25%; major depression, schizophrenia, bipolar disorder). Other notable genes with new high-confidence isoforms include CPLX2 (10%; schizophrenia, epilepsy) and MAOB (9%; targeted for Parkinson's disease treatment). We identified 1,917 clinically relevant genes expressing multiple isoforms in human frontal cortex, where 1,018 had multiple isoforms with different protein coding sequences, demonstrating the need to better understand how individual isoforms from a "single" gene are involved in human health and disease. Exactly 98 of the 1,917 genes are implicated in brain-related diseases, including Alzheimer's disease genes such as APP (A-beta; precursor protein; five), MAPT (tau protein; four), and BIN1 (eight). We also found 99 differentially expressed RNA isoforms between Alzheimer's cases and controls, despite the genes themselves not exhibiting differential expression. Our findings highlight the significant knowledge gaps in RNA isoform diversity and their clinical relevance. Deep long-read RNA sequencing will be necessary going forward to fully comprehend the clinical relevance of individual isoforms for a "single" gene. Key words: RNA isoforms, Clinical relevance, Long reads, Nanopore sequencing, Alzheimer's disease, Human brain.

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“…Abnormal changes in AS make genes produce splicing isoforms after transcription and encode abnormal proteins. Splicing isoforms are related to cancer-related cell migration, cell growth regulation, hormone responsiveness, cell death and changes in gene expression in chemotherapy responses and become tumour biomarkers and molecular targets [ 68 , 69 ]. There is evidence that splicing mutations affecting oncogenes, tumour suppressor genes and other cancer-related genes occur during the initiation and development of cancer and there is a causal link.…”

Section: Perspectivementioning

confidence: 99%

Long non-coding RNAs are involved in alternative splicing and promote cancer progression

et al. 2021

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Alternative splicing (AS) is a key process in which precursor RNAs produce different mature RNAs, and the disorder of AS is a key factor in promoting cancer development. Compared with coding RNA, studies on the functions of long non-coding RNAs (lncRNAs) are far from enough. In fact, lncRNA is an important participant and regulator in the process of AS. On the one hand, lncRNAs regulate cancer progression as AS products of precursor messenger RNA (mRNA), but on the other hand, precursor lncRNA generates cancer-related abnormal splicing variants through AS. In addition, lncRNAs directly or indirectly regulate the AS events of downstream target genes, thus affecting the occurrence and development of cancer. Here, we reviewed how lncRNAs regulate AS and influence oncogenesis in different ways.

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Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation

Cited by 26 publications

References 188 publications

Matrix stiffness triggers chemoresistance through elevated autophagy in pancreatic ductal adenocarcinoma

Matrix stiffness triggers chemoresistance through elevated autophagy in pancreatic ductal adenocarcinoma

Using deep long-read RNAseq in Alzheimer’s disease brain to assess medical relevance of RNA isoform diversity

Long non-coding RNAs are involved in alternative splicing and promote cancer progression

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