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Published in: Cancer Cell International 1/2022

Open Access 01-12-2022 | Breast Cancer | Primary research

ncRNAs-mediated high expression of TIMM8A correlates with poor prognosis and act as an oncogene in breast cancer

Authors: Zhonglin Wang, Shuqin Li, Feng Xu, Jingyue Fu, Jie Sun, XinLi Gan, Chuang Yang, Zhongqi Mao

Published in: Cancer Cell International | Issue 1/2022

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Abstract

Background

Breast cancer is notorious for its increasing incidence for decades. Ascending evidence has demonstrated that translocase of inner mitochondrial membrane (TIMM) proteins play vital roles in progression of several types of human cancer. However, the biological behaviors and molecular mechanisms of TIMM8A in breast cancer remain not fully illustrated.

Methods

Pan-cancer analysis was firstly performed for TIMM8A’s expression and prognosis by Oncomine database. Subsequently, TIMM8A-related noncoding RNAs (ncRNAs) were identified by a series of bioinformatics analyses and dual-luciferase reporter assay, including expression analysis, correlation analysis, and survival analysis. Moreover, the effect of TIMM8A on breast cancer proliferation and apoptosis was evaluated in vitro by CCK-8 assays, EdU cell proliferation assays, JC-1 mitochondrial membrane potential detection assays and Western blot assays and the in vivo effect was revealed through a patient-derived xenograft mouse model.

Results

We found that TIMM8A showed higher expression level in breast cancer and the higher TIMM8A mRNA expression group had a poorer prognosis than the lower TIMM8A group. hsa-circ-0107314/hsa-circ-0021867/hsa-circ-0122013 might be the three most potential upstream circRNAs of hsa-miR-34c-5p/hsa-miR-449a-TIMM8A axis in breast cancer. TIMM8A promotes proliferation of breast cancer cells in vitro and tumor growth in vivo.

Conclusion

Our results confirmed that ncRNAs-mediated upregulation of TIMM8A correlated with poor prognosis and act as an oncogene in breast cancer.
Appendix
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Literature
1.
go back to reference DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin. 2017;67(6):439–48.CrossRef DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin. 2017;67(6):439–48.CrossRef
2.
go back to reference Salhab M, Patani N, Jiang W, Mokbel K. High TIMM17A expression is associated with adverse pathological and clinical outcomes in human breast cancer. Breast Cancer. 2012;19(2):153–60.CrossRef Salhab M, Patani N, Jiang W, Mokbel K. High TIMM17A expression is associated with adverse pathological and clinical outcomes in human breast cancer. Breast Cancer. 2012;19(2):153–60.CrossRef
3.
go back to reference Vander Heiden M, Cantley L, Thompson C. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.CrossRef Vander Heiden M, Cantley L, Thompson C. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.CrossRef
4.
go back to reference Jose C, Bellance N, Rossignol R. Choosing between glycolysis and oxidative phosphorylation: a tumor’s dilemma? Biochem Biophys Acta. 2011;1807(6):552–61.PubMed Jose C, Bellance N, Rossignol R. Choosing between glycolysis and oxidative phosphorylation: a tumor’s dilemma? Biochem Biophys Acta. 2011;1807(6):552–61.PubMed
5.
go back to reference Pelicano H, Zhang W, Liu J, Hammoudi N, Dai J, Xu R-H, Pusztai L, Huang P. Mitochondrial dysfunction in some triple-negative breast cancer cell lines: role of mTOR pathway and therapeutic potential. Breast Cancer Res. 2014;16(5):434.CrossRef Pelicano H, Zhang W, Liu J, Hammoudi N, Dai J, Xu R-H, Pusztai L, Huang P. Mitochondrial dysfunction in some triple-negative breast cancer cell lines: role of mTOR pathway and therapeutic potential. Breast Cancer Res. 2014;16(5):434.CrossRef
6.
go back to reference Ma Y, Bai R-K, Trieu R, Wong L-CJ. Mitochondrial dysfunction in human breast cancer cells and their transmitochondrial cybrids. Biochem Biophys Acta. 2010;1797(1):29–37.PubMed Ma Y, Bai R-K, Trieu R, Wong L-CJ. Mitochondrial dysfunction in human breast cancer cells and their transmitochondrial cybrids. Biochem Biophys Acta. 2010;1797(1):29–37.PubMed
7.
go back to reference Johnson JM, Cotzia P, Fratamico R, Mikkilineni L, Chen J, Colombo D, Mollaee M, Whitaker-Menezes D, Domingo-Vidal M, Lin Z, et al. MCT1 in invasive ductal carcinoma: monocarboxylate metabolism and aggressive breast cancer. Front Cell Dev Biol. 2017;5:27.CrossRef Johnson JM, Cotzia P, Fratamico R, Mikkilineni L, Chen J, Colombo D, Mollaee M, Whitaker-Menezes D, Domingo-Vidal M, Lin Z, et al. MCT1 in invasive ductal carcinoma: monocarboxylate metabolism and aggressive breast cancer. Front Cell Dev Biol. 2017;5:27.CrossRef
8.
go back to reference Bueno MJ, Ruiz-Sepulveda JL, Quintela-Fandino M. Mitochondrial inhibition: a treatment strategy in cancer? Curr Oncol Rep. 2021;23(4):49.CrossRef Bueno MJ, Ruiz-Sepulveda JL, Quintela-Fandino M. Mitochondrial inhibition: a treatment strategy in cancer? Curr Oncol Rep. 2021;23(4):49.CrossRef
9.
go back to reference Zong W-X, Rabinowitz JD, White E. Mitochondria and cancer. Mol Cell. 2016;61(5):667–76.CrossRef Zong W-X, Rabinowitz JD, White E. Mitochondria and cancer. Mol Cell. 2016;61(5):667–76.CrossRef
10.
go back to reference Jensen RE, Dunn CD. Protein import into and across the mitochondrial inner membrane: role of the TIM23 and TIM22 translocons. Biochem Biophys Acta. 2002;1592(1):25–34.CrossRef Jensen RE, Dunn CD. Protein import into and across the mitochondrial inner membrane: role of the TIM23 and TIM22 translocons. Biochem Biophys Acta. 2002;1592(1):25–34.CrossRef
11.
go back to reference van Gisbergen MW, Voets AM, Starmans MHW, de Coo IFM, Yadak R, Hoffmann RF, Boutros PC, Smeets HJM, Dubois L, Lambin P. How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models. Mutat Res Rev Mutat Res. 2015;764:16–30.CrossRef van Gisbergen MW, Voets AM, Starmans MHW, de Coo IFM, Yadak R, Hoffmann RF, Boutros PC, Smeets HJM, Dubois L, Lambin P. How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models. Mutat Res Rev Mutat Res. 2015;764:16–30.CrossRef
12.
go back to reference Lin C-C, Fang C-L, Sun D-P, Hseu Y-C, Uen Y-H, Lin K-Y, Lin Y-C. High expression of mitochondrial intermembrane chaperone TIMM9 represents a negative prognostic marker in gastric cancer. J Formos Med Assoc. 2017;116(6):476–83.CrossRef Lin C-C, Fang C-L, Sun D-P, Hseu Y-C, Uen Y-H, Lin K-Y, Lin Y-C. High expression of mitochondrial intermembrane chaperone TIMM9 represents a negative prognostic marker in gastric cancer. J Formos Med Assoc. 2017;116(6):476–83.CrossRef
13.
go back to reference Cai J, Chen J, Huang L, Wang C, Zhang W, Zhou Q, Sun Z. A TIMM17A regulatory network contributing to breast cancer. Front Genet. 2021;12: 658154.CrossRef Cai J, Chen J, Huang L, Wang C, Zhang W, Zhou Q, Sun Z. A TIMM17A regulatory network contributing to breast cancer. Front Genet. 2021;12: 658154.CrossRef
14.
go back to reference Wang Q, Wen Y-G, Li D-P, Xia J, Zhou C-Z, Yan D-W, Tang H-M, Peng Z-H. Upregulated INHBA expression is associated with poor survival in gastric cancer. Med Oncol. 2012;29(1):77–83.CrossRef Wang Q, Wen Y-G, Li D-P, Xia J, Zhou C-Z, Yan D-W, Tang H-M, Peng Z-H. Upregulated INHBA expression is associated with poor survival in gastric cancer. Med Oncol. 2012;29(1):77–83.CrossRef
15.
go back to reference Heinemeyer T, Stemmet M, Bardien S, Neethling A. Underappreciated roles of the translocase of the outer and inner mitochondrial membrane protein complexes in human disease. DNA Cell Biol. 2019;38(1):23–40.CrossRef Heinemeyer T, Stemmet M, Bardien S, Neethling A. Underappreciated roles of the translocase of the outer and inner mitochondrial membrane protein complexes in human disease. DNA Cell Biol. 2019;38(1):23–40.CrossRef
16.
go back to reference Neighbors A, Moss T, Holloway L, Yu S-H, Annese F, Skinner S, Saneto R, Steet R. Functional analysis of a novel mutation in the TIMM8A gene that causes deafness-dystonia-optic neuronopathy syndrome. Mol Genet Genom Med. 2020;8(3): e1121. Neighbors A, Moss T, Holloway L, Yu S-H, Annese F, Skinner S, Saneto R, Steet R. Functional analysis of a novel mutation in the TIMM8A gene that causes deafness-dystonia-optic neuronopathy syndrome. Mol Genet Genom Med. 2020;8(3): e1121.
17.
go back to reference Xia S, Feng J, Chen K, Ma Y, Gong J, Cai F, Jin Y, Gao Y, Xia L, Chang H, et al. CSCD: a database for cancer-specific circular RNAs. Nucleic Acids Res. 2018;46(D1):D925-d929.CrossRef Xia S, Feng J, Chen K, Ma Y, Gong J, Cai F, Jin Y, Gao Y, Xia L, Chang H, et al. CSCD: a database for cancer-specific circular RNAs. Nucleic Acids Res. 2018;46(D1):D925-d929.CrossRef
18.
go back to reference Ning X, Sun L. Gene network analysis reveals a core set of genes involved in the immune response of Japanese flounder (Paralichthys olivaceus) against Vibrio anguillarum infection. Fish Shellfish Immunol. 2020;98:800–9.CrossRef Ning X, Sun L. Gene network analysis reveals a core set of genes involved in the immune response of Japanese flounder (Paralichthys olivaceus) against Vibrio anguillarum infection. Fish Shellfish Immunol. 2020;98:800–9.CrossRef
19.
go back to reference Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102(43):15545–50.CrossRef Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102(43):15545–50.CrossRef
20.
go back to reference Voabil P, de Bruijn M, Roelofsen LM, Hendriks SH, Brokamp S, van den Braber M, Broeks A, Sanders J, Herzig P, Zippelius A, et al. An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer. Nat Med. 2021;27(7):1250–61.CrossRef Voabil P, de Bruijn M, Roelofsen LM, Hendriks SH, Brokamp S, van den Braber M, Broeks A, Sanders J, Herzig P, Zippelius A, et al. An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer. Nat Med. 2021;27(7):1250–61.CrossRef
21.
go back to reference Zhang X, Lewis MT. Establishment of patient-derived xenograft (PDX) models of human breast cancer. Curr Protoc Mouse Biol. 2013;3(1):21–9.CrossRef Zhang X, Lewis MT. Establishment of patient-derived xenograft (PDX) models of human breast cancer. Curr Protoc Mouse Biol. 2013;3(1):21–9.CrossRef
22.
go back to reference Richardson AL, Wang ZC, De Nicolo A, Lu X, Brown M, Miron A, Liao X, Iglehart JD, Livingston DM, Ganesan S. X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell. 2006;9(2):121–32.CrossRef Richardson AL, Wang ZC, De Nicolo A, Lu X, Brown M, Miron A, Liao X, Iglehart JD, Livingston DM, Ganesan S. X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell. 2006;9(2):121–32.CrossRef
23.
go back to reference Turashvili G, Bouchal J, Baumforth K, Wei W, Dziechciarkova M, Ehrmann J, Klein J, Fridman E, Skarda J, Srovnal J, et al. Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. BMC Cancer. 2007;7:55.CrossRef Turashvili G, Bouchal J, Baumforth K, Wei W, Dziechciarkova M, Ehrmann J, Klein J, Fridman E, Skarda J, Srovnal J, et al. Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. BMC Cancer. 2007;7:55.CrossRef
24.
go back to reference Huang Y, Zhou J, Luo S, Wang Y, He J, Luo P, Chen Z, Liu T, Tan X, Ou J, et al. Identification of a fluorescent small-molecule enhancer for therapeutic autophagy in colorectal cancer by targeting mitochondrial protein translocase TIM44. Gut. 2018;67(2):307–19.CrossRef Huang Y, Zhou J, Luo S, Wang Y, He J, Luo P, Chen Z, Liu T, Tan X, Ou J, et al. Identification of a fluorescent small-molecule enhancer for therapeutic autophagy in colorectal cancer by targeting mitochondrial protein translocase TIM44. Gut. 2018;67(2):307–19.CrossRef
25.
go back to reference Tang WK, Borgnia MJ, Hsu AL, Esser L, Fox T, de Val N, Xia D. Structures of AAA protein translocase Bcs1 suggest translocation mechanism of a folded protein. Nat Struct Mol Biol. 2020;27(2):202–9.CrossRef Tang WK, Borgnia MJ, Hsu AL, Esser L, Fox T, de Val N, Xia D. Structures of AAA protein translocase Bcs1 suggest translocation mechanism of a folded protein. Nat Struct Mol Biol. 2020;27(2):202–9.CrossRef
26.
go back to reference Bonora E, Evangelisti C, Bonichon F, Tallini G, Romeo G. Novel germline variants identified in the inner mitochondrial membrane transporter TIMM44 and their role in predisposition to oncocytic thyroid carcinomas. Br J Cancer. 2006;95(11):1529–36.CrossRef Bonora E, Evangelisti C, Bonichon F, Tallini G, Romeo G. Novel germline variants identified in the inner mitochondrial membrane transporter TIMM44 and their role in predisposition to oncocytic thyroid carcinomas. Br J Cancer. 2006;95(11):1529–36.CrossRef
27.
go back to reference Zhang X, Han S, Zhou H, Cai L, Li J, Liu N, Liu Y, Wang L, Fan C, Li A, et al. TIMM50 promotes tumor progression via ERK signaling and predicts poor prognosis of non-small cell lung cancer patients. Mol Carcinog. 2019;58(5):767–76.CrossRef Zhang X, Han S, Zhou H, Cai L, Li J, Liu N, Liu Y, Wang L, Fan C, Li A, et al. TIMM50 promotes tumor progression via ERK signaling and predicts poor prognosis of non-small cell lung cancer patients. Mol Carcinog. 2019;58(5):767–76.CrossRef
28.
go back to reference Nagley P, Higgins GC, Atkin JD, Beart PM. Multifaceted deaths orchestrated by mitochondria in neurones. Biochem Biophys Acta. 2010;1802(1):167–85.PubMed Nagley P, Higgins GC, Atkin JD, Beart PM. Multifaceted deaths orchestrated by mitochondria in neurones. Biochem Biophys Acta. 2010;1802(1):167–85.PubMed
29.
go back to reference McBride HM, Neuspiel M, Wasiak S. Mitochondria: more than just a powerhouse. Curr Biol. 2006;16(14):R551–60.CrossRef McBride HM, Neuspiel M, Wasiak S. Mitochondria: more than just a powerhouse. Curr Biol. 2006;16(14):R551–60.CrossRef
Metadata
Title
ncRNAs-mediated high expression of TIMM8A correlates with poor prognosis and act as an oncogene in breast cancer
Authors
Zhonglin Wang
Shuqin Li
Feng Xu
Jingyue Fu
Jie Sun
XinLi Gan
Chuang Yang
Zhongqi Mao
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2022
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-022-02595-x

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