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Micropeptide ASAP encoded by LINC00467 promotes colorectal cancer progression by directly modulating ATP synthase activity
Qiwei Ge, … , Shujie Chen, Liangjing Wang
Qiwei Ge, … , Shujie Chen, Liangjing Wang
Published September 30, 2021
Citation Information: J Clin Invest. 2021;131(22):e152911. https://doi.org/10.1172/JCI152911.
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Research Article Gastroenterology Oncology Article has an altmetric score of 19

Micropeptide ASAP encoded by LINC00467 promotes colorectal cancer progression by directly modulating ATP synthase activity

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Abstract

Emerging evidence has shown that open reading frames inside long noncoding RNAs (lncRNAs) could encode micropeptides. However, their roles in cellular energy metabolism and tumor progression remain largely unknown. Here, we identified a 94 amino acid–length micropeptide encoded by lncRNA LINC00467 in colorectal cancer. We also characterized its conservation across higher mammals, localization to mitochondria, and the concerted local functions. This peptide enhanced the ATP synthase construction by interacting with the subunits α and γ (ATP5A and ATP5C), increased ATP synthase activity and mitochondrial oxygen consumption rate, and thereby promoted colorectal cancer cell proliferation. Hence, this micropeptide was termed ATP synthase–associated peptide (ASAP). Furthermore, loss of ASAP suppressed patient-derived xenograft growth with attenuated ATP synthase activity and mitochondrial ATP production. Clinically, high expression of ASAP and LINC00467 predicted poor prognosis of colorectal cancer patients. Taken together, our findings revealed a colorectal cancer–associated micropeptide as a vital player in mitochondrial metabolism and provided a therapeutic target for colorectal cancer.

Authors

Qiwei Ge, Dingjiacheng Jia, Dong Cen, Yadong Qi, Chengyu Shi, Junhong Li, Lingjie Sang, Luo-jia Yang, Jiamin He, Aifu Lin, Shujie Chen, Liangjing Wang

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Figure 8

Targeting ASAP suppresses the growth of PDXs.

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Targeting ASAP suppresses the growth of PDXs.
(A) Schematic diagram show...
(A) Schematic diagram showing the CRISPR/Cas9 system–based strategy to disrupt ASAP of PDXs. Three days after tumor inoculation, mice received 3 weeks of intratumoral injection of either ASAP-targeted CRISPR/Cas9 (Cas9-sgASAP) vector plus delivery buffer (purple arrows) or CRISPR v2 vector plus delivery buffer (blue arrows). (B and C) In vivo generated tumors (B) and tumor weight (C) of PDX models are shown. Independent samples, 2-sided Student’s t test. ***P < 0.001. (D) Representative IHC staining in tumors from PDX model are shown. Scale bars: 200 μm. (E) The relative intensities of IHC (Figure 8D) were quantified by ImageJ software (version 1.51) in 10 random fields from 5 tumors in each group. Data are presented as mean ± SD from n = 5 tumor samples per group. Independent samples, 2-sided Student’s t test. **P < 0.01; ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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