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LINC00337 promotes tumor angiogenesis in colorectal cancer by recruiting DNMT1, which suppresses the expression of CNN1

Cancer Gene Therapy volume 28, pages 1285–1297 (2021)Cite this article

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Abstract

Colorectal cancer (CRC) is one of the most common human malignancies. An increasing body of evidence has revealed the important roles long noncoding RNA (lncRNA) plays in the growth dynamics of CRC cells. In this study, we aimed to define the role of LINC00337 in the malignant phenotypes, especially angiogenesis, of CRC and clarify the underlying molecular basis. Bioinformatic analyses identified promoter region methylation of CNN1 in CRC, which was further validated by BSP and MSP assays. Loss- and gain- of function approaches were used to determine the roles of CNN1 and LINC00337 in vitro and in vivo. MTT-based method, Transwell migration/invasion assays, and tube formation assay were adopted to evaluate the cancer cell proliferation, migration/invasion, and proangiogenetic potency respectively in vitro. The tumor growth, microvascular density (MVD) and markers of proliferation (Ki67) and angiogenesis (VEGF) were quantified in nude mice xenografted with CRC cells. It was found that CNN1 downregulation and LINC00337 overexpression occurred in CRC tissues and cells. Besides, the CNN1 promoter region was hypermethylated in CRC. CNN1 overexpression or LINC00337 knockdown restricted CRC cell proliferation, migration/invasion, and proangiogenetic potency in vitro, which was substantiated by the in vivo experiments evidenced by facilitated tumor growth and MVD as well as elevated Ki67 and VEGF. Furthermore, our mechanistic evidence revealed that LINC00337 recruited DNMT1 to the promoter region of CNN1 and restricted the transcription of CNN1. Taken together, this study indicates that LINC00337 facilitates the tumorigenesis and angiogenesis in CRC via recruiting DNMT1 to inhibit the expression of CNN1.

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Fig. 1: The CNN1 is poorly expressed and its promoter region is hypermethylated in CRC.
Fig. 2: CNN1 elevation inhibits in the malignant phenotypes of CRC cells in vitro.
Fig. 3: CNN1 silencing promotes tumorigenesis and tumor angiogenesis in vivo.
Fig. 4: LINC00337 recruits DNMT1 to promote CNN1 promoter region hypermethylation and inhibit CNN1 transcription.
Fig. 5: Silencing of LINC00337 suppresses CRC cell proliferation, migration, invasion, and proangiogenetic potency in vitro.
Fig. 6: LINC00337 promotes tumorigenesis in vivo via increasing CNN1 promoter region methylation which subsequently suppresses CNN1 transcription.
Fig. 7: Mechanism graph of the modulatory network and function of LINC00337 in regulating angiogenesis in CRC.

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The datasets generated/analysed during the current study are available.

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Acknowledgements

We acknowledge and appreciate our colleagues for their valuable efforts and comments on this paper.

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Authors and Affiliations

  1. Department of Gastroenterology, Linyi People’s Hospital, 276000, Linyi, P. R. China

    Xiangming Xu, Jiao Nie, Lin Lu, Chao Du, Fansheng Meng & Duannuo Song

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  1. Xiangming Xu
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  2. Jiao Nie
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  3. Lin Lu
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  4. Chao Du
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  5. Fansheng Meng
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  6. Duannuo Song
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Contributions

XX and JN designed the study. LL and CD collated the data, FM and DS carried out data analyses and produced the initial draft of the manuscript. XX and JN contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Duannuo Song.

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The authors declare that they have no conflict of interest.

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This study was performed under the approval of the Ethics Committee of Linyi People’s Hospital and all participated patients have submitted written informed consents. All animal studies were accomplished under the protocol approved by the Institutional Animal Care and Use Committee of Linyi People’s Hospital.

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Xu, X., Nie, J., Lu, L. et al. LINC00337 promotes tumor angiogenesis in colorectal cancer by recruiting DNMT1, which suppresses the expression of CNN1. Cancer Gene Ther 28, 1285–1297 (2021). https://doi.org/10.1038/s41417-020-00277-2

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