Hypoxia induced LUCAT1/PTBP1 axis modulates cancer cell viability and chemotherapy response

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Abstract

Background

Hypoxic tumors are refractory to DNA damage drugs. However, the underlying mechanism has yet to be elucidated. We aimed to identify lncRNAs that upregulated under hypoxia and their effects on colorectal cancer (CRC).

Methods

CRC cells were treated with 1% O ₂ to identify lncRNAs that upregulated under hypoxia. We integrated these lncRNAs with RNA-seq of 4 paired CRC tissues and TCGA data to get candidate lncRNAs. Multiple in vitro and in vivo assays were used to explore the role of LUCAT1 in CRC.

Results

We identified a hypoxia-induced lncRNA LUCAT1 that facilitated the growth of CRC cells and contributed to drug resistance of CRC cells both in vitro and in vivo. Mechanically, LUCAT1 interacts with polypyrimidine tract binding protein 1 (PTBP1) in CRC cells, facilitates the association of a set of DNA damage related genes with PTBP1, thus resulting in altered alternative splicing of these genes. Moreover, ectopic expression of PTBP1 in CRC cells with knockdown of LUCAT1 abrogated the effects induced by LUCAT1 knockdown. Chemotherapeutics drug combined with LUCAT1 knockdown via antisense oligonucleotides (ASO) would get a better outcome in vivo, compared with group treated with chemotherapeutic drug only. Notably, LUCAT1 is upregulated in CRC tissues, compared to adjacent normal tissues; and CRC patients with higher LUCAT1 have a worse prognosis and poorly responded to chemotherapy in the clinic.

Conclusions

Our data suggested CRC cells utilizes LUCAT1 to develop resistance to DNA damage drugs, and disrupting the LUCAT1/PTBP1 axis might be a promising therapeutic strategy for refractory hypoxic tumors.

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Most cited references 22

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Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene

F M Buffa, Adrian Harris, C M L West … (2010)

Background: There is a need to develop robust and clinically applicable gene expression signatures. Hypoxia is a key factor promoting solid tumour progression and resistance to therapy; a hypoxia signature has the potential to be not only prognostic but also to predict benefit from particular interventions. Methods: An approach for deriving signatures that combine knowledge of gene function and analysis of in vivo co-expression patterns was used to define a common hypoxia signature from three head and neck and five breast cancer studies. Previously validated hypoxia-regulated genes (seeds) were used to generate hypoxia co-expression cancer networks. Results: A common hypoxia signature, or metagene, was derived by selecting genes that were consistently co-expressed with the hypoxia seeds in multiple cancers. This was highly enriched for hypoxia-regulated pathways, and prognostic in multivariate analyses. Genes with the highest connectivity were also the most prognostic, and a reduced metagene consisting of a small number of top-ranked genes, including VEGFA, SLC2A1 and PGAM1, outperformed both a larger signature and reported signatures in independent data sets of head and neck, breast and lung cancers. Conclusion: Combined knowledge of multiple genes' function from in vitro experiments together with meta-analysis of multiple cancers can deliver compact and robust signatures suitable for clinical application.

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RBPmap: a web server for mapping binding sites of RNA-binding proteins

Inbal Paz, Idit Kosti, Manuel Ares … (2014)

Regulation of gene expression is executed in many cases by RNA-binding proteins (RBPs) that bind to mRNAs as well as to non-coding RNAs. RBPs recognize their RNA target via specific binding sites on the RNA. Predicting the binding sites of RBPs is known to be a major challenge. We present a new webserver, RBPmap, freely accessible through the website http://rbpmap.technion.ac.il/ for accurate prediction and mapping of RBP binding sites. RBPmap has been developed specifically for mapping RBPs in human, mouse and Drosophila melanogaster genomes, though it supports other organisms too. RBPmap enables the users to select motifs from a large database of experimentally defined motifs. In addition, users can provide any motif of interest, given as either a consensus or a PSSM. The algorithm for mapping the motifs is based on a Weighted-Rank approach, which considers the clustering propensity of the binding sites and the overall tendency of regulatory regions to be conserved. In addition, RBPmap incorporates a position-specific background model, designed uniquely for different genomic regions, such as splice sites, 5’ and 3’ UTRs, non-coding RNA and intergenic regions. RBPmap was tested on high-throughput RNA-binding experiments and was proved to be highly accurate.

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Genetics, diagnosis and management of colorectal cancer (Review)

Marina De Rosa, UGO PACE, DANIELA REGA … (2015)

Colorectal cancer (CRC) is the third most common type of cancer worldwide and a leading cause of cancer death. Surgery represents the mainstay of treatment in early cases but often patients are primarily diagnosed in an advanced stage of disease and sometimes also distant metastases are present. Neoadjuvant therapy is therefore needed but drug resistance may influence response and concur to recurrent disease. At molecular level, it is a very heterogeneous group of diseases with about 30% of hereditary or familial cases. During colorectal adenocarcinomas development, epithelial cells from gastrointestinal trait acquire sequential genetic and epigenetic mutations in specific oncogenes and/or tumour suppressor genes, causing CRC onset, progression and metastasis. Molecular characterization of cancer associated mutations gives valuable information about disease prognosis and response to the therapy. Very early diagnosis and personalized care, as well as a better knowledge of molecular basis of its onset and progression, are therefore crucial to obtain a cure of CRC. In this review, we describe updated genetics, current diagnosis and management of CRC pointing out the extreme need for a multidisciplinary approach to achieve the best results in patient outcomes.

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Author and article information

Contributors

Ye Xu: xuye021@163.com

Linhui Liang: lianglinhui@fudan.edu.cn

Xianghuo He: xhhe@fudan.edu.cn

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 21 January 2020

Publication date PMC-release: 21 January 2020

Publication date Collection: 2020

Volume: 19

Electronic Location Identifier: 11

Affiliations

[1 ]ISNI 0000 0004 0619 8943, GRID grid.11841.3d, Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, ; Shanghai, 200032 China

[2 ]Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032 China

[3 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, , Fudan University, ; Shanghai, 200032 China

Article

Publisher ID: 1122

DOI: 10.1186/s12943-019-1122-z

PMC ID: 6971890

PubMed ID: 31964396

SO-VID: 6a9eedca-31b3-4cd3-9f43-bf19b54fb4d4

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 27 September 2019

Date accepted : 23 December 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81672366

Award ID: 81672774

Award ID: 81790252

Award Recipient : Linhui Liang Xianghuo He

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hypoxia,lncrna,lucat1,ptbp1,alternative splicing,chemoresistance

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hypoxia, lncrna, lucat1, ptbp1, alternative splicing, chemoresistance

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Hypoxia induced LUCAT1/PTBP1 axis modulates cancer cell viability and chemotherapy response

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Abstract

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Karger: Oncology

Most cited references 22

Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene

RBPmap: a web server for mapping binding sites of RNA-binding proteins

Genetics, diagnosis and management of colorectal cancer (Review)

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Cited by 74

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