MRPL33 and its splicing regulator hnRNPK are required for mitochondria function and implicated in tumor progression

Liu, L; Luo, Chunling; Luo, Yangping; Chen, L; Liu, Y; Wang, Y; Han, Jun; Zhang, Y; Wei, Ning; Xie, Zhiqin; Wu, Weijie; Wu, Guohao; Feng, Yuanyuan

doi:10.1038/onc.2017.314

Cited by 42 publications

(51 citation statements)

References 25 publications

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“…Functional studies conducted on the UPF3A minigene further demonstrated that they bind to enhancer elements within the alternative exon and activate its inclusion. Taken together, our findings provided strong evidence that CHERP and SR140 can function both positively and negatively in regulating exon inclusion in cancer cells, just like SR proteins and hnRNP proteins …”

Section: Discussionsupporting

confidence: 54%

“…Levels of splicing factors such as SRSF1, SRSF6, SRSF10, hnRNPK or hnRNPLL are significantly altered in many types of cancer including CRC . Therefore, it is not surprising that dysregulated AS events can contribute to almost all hallmarks of cancer, including sustained proliferation and evasion of apoptosis .…”

Section: Discussionmentioning

confidence: 99%

“…RT‐PCR and qPCR were performed as previously described . In vivo crosslinking and immunoprecipitation (CLIP) of mRNA bound to CHERP or SR140 proteins was performed as previously described .…”

Section: Methodsmentioning

confidence: 99%

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U2‐related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation

Wang

Liu

et al. 2019

Intl Journal of Cancer

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Dysregulation of calcium homeostasis endoplasmic reticulum protein (CHERP) has been implicated in several cancers, but it remains elusive how CHERP contributes to cancer cell proliferation and cancer development. Here, we observed that CHERP and its binding partner SR140 are significantly upregulated in human clinical colorectal cancer tissues (CRC). CHERP and SR140 could form a protein complex to stabilize each other. Knockdown of CHERP or SR140 triggers double‐stranded DNA breaks and cell death. Furthermore, UPF3A, the RNA surveillance factor, was identified as a splicing target of CHERP and SR140, which bind specifically to the regulated exon4 and modulate UPF3A splicing. UPF3A knockdown recapitulates CHERP/SR140 depletion both in vitro and in mice. Importantly, overexpression of UPF3A significantly rescues proliferation defect of CHERP/SR140‐depleted cells. These results confirmed that the effect of CHERP/SR140 in promoting tumorigenesis was partially mediated by UPF3A. Extending these results, upregulation of CHERP/SR140 observed in CRC remarkably parallels increased inclusion of UPF3A exon4. Together, our study clarifies how CHERP/SR140 exert an oncogenic role in CRC development partially through regulating expression of UPF3A variants.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

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U2‐related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation

Wang

Liu

et al. 2019

Intl Journal of Cancer

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“…5 Dysregulation of HNRNP proteins is known to help cancer progression through their nonsplicing functions. 6 For example, HNRNPK has been shown to promote proliferation of colorectal cancer cells by regulating not only pre-mRNA splicing of MRPL33, 7 but also transcription of CDKN2B 8 and MMP2, 9 mRNA stability of CDK6, 10 and mRNA translation of BTK. 11 In this study, we address the role of HNRNPLL in proliferation of colorectal cancer cells and demonstrate that HNRNPLL stabilizes mRNA encoding regulators of DNA replication and enhances cell cycle progression.…”

mentioning

confidence: 99%

HNRNPLL stabilizes mRNA for DNA replication proteins and promotes cell cycle progression in colorectal cancer cells

et al. 2018

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Heterogeneous nuclear ribonucleoprotein L‐like (HNRNPLL), an RNA‐binding protein that regulates alternative splicing of pre‐mRNA, has been shown to regulate differentiation of lymphocytes, as well as metastasis of colorectal cancer cells. Here, we show that HNRNPLL promotes cell cycle progression and, hence, proliferation of colorectal cancer cells. Functional annotation analysis of those genes whose expression levels were changed threefold or more in RNA sequencing analysis between SW480 cells overexpressing HNRNPLL and those knocked down for HNRNPLL revealed enrichment of DNA replication‐related genes by HNRNPLL overexpression. Among 13 genes detected in the DNA replication pathway, PCNA,RFC3 and FEN1 showed reproducible upregulation by HNRNPLL overexpression both at mRNA and at protein levels in SW480 and HT29 cells. Importantly, knockdown of any of these genes alone suppressed the proliferation‐promoting effect induced by HNRNPLL overexpression. RNA‐immunoprecipitation assay presented a binding of FLAG‐tagged HNRNPLL to mRNA of these genes, and HNRNPLL overexpression significantly suppressed the downregulation of these genes during 12 h of actinomycin D treatment, suggesting a role of HNRNPLL in mRNA stability. Finally, analysis of a public RNA sequencing dataset of clinical samples suggested a link between overexpression of HNRNPLL and that of PCNA,RFC3 and FEN1. This link was further supported by immunohistochemistry of colorectal cancer clinical samples, whereas expression of CDKN1A, which is known to inhibit the cooperative function of PCNA, RFC3 and FEN1, was negatively associated with HNRNPLL expression. These results indicate that HNRNPLL stabilizes mRNA encoding regulators of DNA replication and promotes colorectal cancer cell proliferation.

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“…Among these top significant prognostic AS events, some have already been experimentally validated in multiple oncogenic processes by previous investigations. 32 28,29 Besides, the ME event of SLC39A14 with an HR of 0.43 played a role of tumor-suppressor in colorectal cancer.…”

Section: Identification Of Survivalassociated As Events In Prcc Cohortmentioning

confidence: 99%

Identification of novel prognostic alternative splicing signature in papillary renal cell carcinoma

Duan

Zhang

2019

J of Cellular Biochemistry

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Papillary renal cell carcinoma (pRCC) is a heterogeneous disease containing multifocal or solitary tumors with an aggressive phenotype. Increasing evidence has indicated the involvement of aberrant splicing variants in renal cell cancer, while systematic profiling of aberrant alternative splicing (AS) in pRCC was lacking and largely unknown. In the current study, comprehensive profiling of AS events were performed based on the integration of pRCC cohort from the Cancer Genome Atlas database and SpliceSeq software. With rigorous screening and univariate Cox analysis, a total of 2077 prognoses AS events from 1642 parent genes were identified. Then, stepwise least absolute shrinkage and selection operator method‐penalized Cox regression analyses with 10‐fold cross‐validation followed by multivariate Cox regression were used to construct the prognostic AS signatures within each AS type. And a final 21 AS event‐based signature was proposed which showed potent prognostic capability in stratifying patients into low‐ and high‐risk subgroups (P < .0001). Furthermore, time‐dependent receiver operating characteristics curves confirmed that the final AS signature was effective and robust in predicting overall survival for pRCC patients with the area under the curve above 0.9 from 1 to 5 years. In addition, splicing correlation network was built to uncover the potential regulatory pattern among prognostic splicing factors and candidate AS events. Besides, gene set enrichment analysis revealed the involvement of these candidates AS events in tumor‐related pathways including extracellular matrix organization, oxidative phosphorylation, and P53 signaling pathways. Taken together, our results could contribute to elucidating the underlying mechanism of AS in the oncogenesis process and broaden the novel field of prognostic and clinical application of molecule‐targeted approaches in pRCC.

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MRPL33 and its splicing regulator hnRNPK are required for mitochondria function and implicated in tumor progression

Cited by 42 publications

References 25 publications

U2‐related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation

U2‐related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation

HNRNPLL stabilizes mRNA for DNA replication proteins and promotes cell cycle progression in colorectal cancer cells

Identification of novel prognostic alternative splicing signature in papillary renal cell carcinoma

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