MCCC2 is a novel mediator between mitochondria and telomere and functions as an oncogene in colorectal cancer.
MCCC2 is a novel mediator between mitochondria and telomere and functions as an oncogene in colorectal cancer.
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DOI：
10.1186/s11658-023-00487-0
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发表时间：
2023-10-12
影响因子：
8.3
通讯作者：
Chen, Daici
中科院分区：
文献类型：
--
作者：
Liu, Wanjun;Chen, Si;Xie, Wenqing;Wang, Qian;Luo, Qianxin;Huang, Minghan;Gu, Minyi;Lan, Ping;Chen, Daici
线粒体基因MCCC 2是3-甲基巴豆酰辅酶A羧化酶异二聚体的一个亚基，在亮氨酸和异戊酸的催化中起着关键作用。分子机制和预后价值仍需要在特定癌症（包括结直肠癌（CRC））的背景下进行探索。进行体外和体内基于细胞的测定以探索MCCC 2在CRC细胞增殖、侵袭和迁移中的作用。线粒体形态，膜电位，细胞内活性氧（ROS），端粒酶活性，端粒长度进行了检查和分析。通过免疫共沉淀（CO-IP）检测蛋白复合物的形成。透射电镜观察线粒体形态。使用癌症基因组图谱（TCGA）CRC队列分析、qRT-PCR和免疫组织化学（IHC）检查MCCC 2表达水平。通过卡方检验分析MCCC 2表达与各种临床特征之间的关联。采用Kaplan-Meier法分析结直肠癌患者的总生存期（OS）。MCCC 2的异位过表达促进细胞增殖、侵袭和迁移，而MCCC 2敲低（KD）或敲除（KO）抑制细胞增殖、侵袭和迁移。MCCC 2 KD或KO导致细胞中线粒体数量减少，但不影响总ATP产生。线粒体融合标志物MFN 1、MFN 2和OPA 1在MCCC 2 KD或KO细胞中均上调，这与更显著的线粒体融合现象一致。有趣的是，MCCC 2 KD或KO细胞的端粒长度比对照细胞减少更多。此外，我们发现MCCC 2可以与端粒结合蛋白TRF 2特异性地形成复合物，并且MCCC 2 KD或KO不影响端粒酶逆转录酶（TERT）的表达或活性。MCCC 2在结直肠癌组织中表达增高，MCCC 2高表达者预后良好。总之，我们将MCCC 2鉴定为线粒体和端粒之间的新介质，并为CRC分层提供了额外的生物标志物。在线版本包含补充材料，可通过10.1186/s11658-023-00487-0获得。
The mitochondrial gene MCCC2, a subunit of the heterodimer of 3-methylcrotonyl-CoA carboxylase, plays a pivotal role in catabolism of leucine and isovaleric acid. The molecular mechanisms and prognostic value still need to be explored in the context of specific cancers, including colorectal cancer (CRC). In vitro and in vivo cell-based assays were performed to explore the role of MCCC2 in CRC cell proliferation, invasion, and migration. Mitochondrial morphology, membrane potential, intracellular reactive oxygen species (ROS), telomerase activity, and telomere length were examined and analyzed accordingly. Protein complex formation was detected by co-immunoprecipitation (CO-IP). Mitochondrial morphology was observed by transmission electron microscopy (TEM). The Cancer Genome Atlas (TCGA) CRC cohort analysis, qRT-PCR, and immunohistochemistry (IHC) were used to examine the MCCC2 expression level. The association between MCCC2 expression and various clinical characteristics was analyzed by chi-square tests. CRC patients’ overall survival (OS) was analyzed by Kaplan–Meier analysis. Ectopic overexpression of MCCC2 promoted cell proliferation, invasion, and migration, while MCCC2 knockdown (KD) or knockout (KO) inhibited cell proliferation, invasion, and migration. MCCC2 KD or KO resulted in reduced mitochondria numbers, but did not affect the gross ATP production in the cells. Mitochondrial fusion markers MFN1, MFN2, and OPA1 were all upregulated in MCCC2 KD or KO cells, which is in line with a phenomenon of more prominent mitochondrial fusion. Interestingly, telomere lengths of MCCC2 KD or KO cells were reduced more than control cells. Furthermore, we found that MCCC2 could specifically form a complex with telomere binding protein TRF2, and MCCC2 KD or KO did not affect the expression or activity of telomerase reverse transcriptase (TERT). Finally, MCCC2 expression was heightened in CRC, and patients with higher MCCC2 expression had favorable prognosis. Together, we identified MCCC2 as a novel mediator between mitochondria and telomeres, and provided an additional biomarker for CRC stratification. The online version contains supplementary material available at 10.1186/s11658-023-00487-0.
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影响因子：
16.6
作者：
de Cárcer G;Venkateswaran SV;Salgueiro L;El Bakkali A;Somogyi K;Rowald K;Montañés P;Sanclemente M;Escobar B;de Martino A;McGranahan N;Malumbres M;Sotillo R
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DOI：
10.18632/aging.101089
发表时间：
2016-10-22
期刊：
Aging
影响因子：
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DOI：
10.1007/978-3-030-49844-3_3
发表时间：
2021-01-01
期刊：
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影响因子：
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作者：
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影响因子：
29
作者：
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