A splicing variant of Merlin promotes metastasis in hepatocellular carcinoma

Luo, Zaili; Cheng, Shuqun; Shi, Jie; Zhang, Hui‐Lu; Zhang, Cunzhen; Chen, Haiyang; Qiu, Bijun; Tang, Liang; Hu, Congli; Wang, Hongyang; Li, Zhong

doi:10.1038/ncomms9457

Cited by 33 publications

(42 citation statements)

References 42 publications

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“…According to our previous RNA-seq analysis, the expression of more than 2000 genes was affected differentially by NBT, and further bioinformatics analysis showed that NBT could affect RNA-binding proteins (RBPs) to regulate alternative splicing (AS) events (data not shown). As one of the post-transcriptional gene regulatory mechanisms, AS enables a single gene to produce multiple messenger RNA variants and distinct protein isoforms, sometimes with different or even opposing roles in the development of tumors, such as proliferation, apoptosis, angiogenesis, drug resistance, and metastasis [23][24][25] . RNA-binding proteins, which are involved in the AS process, have many functions in biologic processes, deregulation of RBP affects every step of cancer development, such as sustained cell proliferation, evasion of apoptosis, avoiding immune surveillance, inducing angiogenesis, and activating metastasis 26,27 ; mounting evidence supports a vital role for RBPs in tumor growth and metastasis [28][29][30] .…”

Section: Discussionmentioning

confidence: 99%

The natural compound neobractatin inhibits tumor metastasis by upregulating the RNA-binding-protein MBNL2

Zhang

Zheng

et al. 2019

Cell Death Dis

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Tumor metastasis is the predominant cause of lethality in cancer. We found that Neobractatin (NBT), a natural compound isolated from Garcinia bracteata, could efficiently inhibit breast and lung cancer cells metastasis. However, the mechanisms of NBT inhibiting cancer metastasis remain unclear. Based on the RNA-sequencing result and transcriptome analysis, Muscleblind-like 2 (MBNL2) was found to be significantly upregulated in the cells treated with NBT. The Cancer Genome Atlas (TCGA) database analysis indicated that the expression of MBNL2 in breast and lung carcinoma tumor tissues was significantly lower compared to normal tissues. We thus conducted to investigate the antimetastatic role of MBNL2. MBNL2 overexpression mimicked the effect of NBT on breast cancer and lung cancer cell motility and metastasis, in addition significantly enhanced the inhibition effect of NBT. MBNL2 knockdown furthermore partially eliminated the inhibitory effect of NBT on metastasis. Mechanistically, we demonstrated that NBT-and MBNL2mediated antimetastasis regulation significantly correlated with the pAKT/epithelial-mesenchymal transition (EMT) pathway. Subsequent in vivo study showed the same metastasis inhibition effect in NBT and MBNL2 in MDA-MB-231 xenografts mouse model. This study suggest that NBT possesses significant antitumor activity in breast and lung cancer cells that is partly mediated through the MBNL2 expression and enhancement in metastasis via the pAKT/EMT signaling pathway.

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Section: Discussionmentioning

confidence: 99%

The natural compound neobractatin inhibits tumor metastasis by upregulating the RNA-binding-protein MBNL2

Zhang

Zheng

et al. 2019

Cell Death Dis

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“…Although interest in defining cancer‐associated AS continues to increase, the specific biological function harnessed by many of the AS variants in conferring oncogenic advantages remained minimally investigated. To date, there are only a handful of such studies described in HCC . Moreover, although many observational studies have illustrated presence of aberrantly spliced genes in human cancers, the AS landscape of human HCC remains largely unexplored.…”

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confidence: 99%

Long‐Read RNA Sequencing Identifies Alternative Splice Variants in Hepatocellular Carcinoma and Tumor‐Specific Isoforms

Chen

Gao

et al. 2019

Hepatology

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Alternative splicing (AS) allows generation of cell type–specific mRNA transcripts and contributes to hallmarks of cancer. Genome‐wide analysis for AS in human hepatocellular carcinoma (HCC), however, is limited. We sought to obtain a comprehensive AS landscape in HCC and define tumor‐associated variants. Single‐molecule real‐time long‐read RNA sequencing was performed on patient‐derived HCC cells, and presence of splice junctions was defined by SpliceMap‐LSC‐IDP algorithm. We obtained an all‐inclusive map of annotated AS variants and further discovered 362 alternative spliced variants that are not previously reported in any database (neither RefSeq nor GENCODE). They were mostly derived from intron retention and early termination codon with an in‐frame open reading frame in 81.5%. We corroborated many of these predicted unannotated and annotated variants to be tumor specific in an independent cohort of primary HCC tumors and matching nontumoral liver. Using the combined Sanger sequencing and TaqMan junction assays, unique and common expressions of spliced variants including enzyme regulators (ARHGEF2, SERPINH1), chromatin modifiers (DEK, CDK9, RBBP7), RNA‐binding proteins (SRSF3, RBM27, MATR3, YBX1), and receptors (ADRM1, CD44v8‐10, vitamin D receptor, ROR1) were determined in HCC tumors. We further focused functional investigations on ARHGEF2 variants (v1 and v3) that arise from the common amplified site chr.1q22 of HCC. Their biological significance underscores two major cancer hallmarks, namely cancer stemness and epithelial‐to‐mesenchymal transition–mediated cell invasion and migration, although v3 is consistently more potent than v1. Conclusion: Alternative isoforms and tumor‐specific isoforms that arise from aberrant splicing are common during the liver tumorigenesis. Our results highlight insights gained from the analysis of AS in HCC.

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“…Moesin-ezrin-radixin-like protein (Merlin) is a tumor suppressor that participates in the regulation of cell proliferation, motility and survival [163]. Merlin is codified by the Nf2 gene, which is heterozygous in mice and is related to the development of highly metastatic malignant tumors [163].…”

Section: Merlinmentioning

confidence: 99%

Influence of transcriptional variants on metastasis

Poloni

Bonatto

2018

RNA Biology

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Cancer metastasis is defined as the dissemination of malignant cells from the primary tumor site, leading to colonization of distant organs and the establishment of a secondary tumor. Metastasis is frequently associated with chemoresistance and is the major cause of cancer-related mortality. Metastatic cells need to acquire the ability to resist to stresses provided by different environments, such as reactive oxygen species, shear stress, hemodynamic forces, stromal composition, and immune responses, to colonize other tissues. Hence, only a small population of cells has a metastasis-initiating potential. Several studies have revealed the misregulation of transcriptional variants during cancer progression, and many splice events can be used to distinguish between normal and tumoral tissue. These variants, which are abnormally expressed in malignant cells, contribute to an adaptive response of tumor cells and the success of the metastatic cascade, promoting an anomalous cell cycle, cellular adhesion, resistance to death, cell survival, migration and invasion. Understanding the different aspects of splicing regulation and the influence of transcriptional variants that control metastatic cells is critical for the development of therapeutic strategies. In this review, we describe how transcriptional variants contribute to metastatic competence and discuss how targeting specific isoforms may be a promising therapeutic strategy.

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A splicing variant of Merlin promotes metastasis in hepatocellular carcinoma

Cited by 33 publications

References 42 publications

The natural compound neobractatin inhibits tumor metastasis by upregulating the RNA-binding-protein MBNL2

The natural compound neobractatin inhibits tumor metastasis by upregulating the RNA-binding-protein MBNL2

Long‐Read RNA Sequencing Identifies Alternative Splice Variants in Hepatocellular Carcinoma and Tumor‐Specific Isoforms

Influence of transcriptional variants on metastasis

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