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Troponin C-1 Activated by E2F1 Accelerates Gastric Cancer Progression via Regulating TGF-β/Smad Signaling

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Abstract

Background

Troponin C-1 (TNNC1) has been previously characterized as an oncogenic gene.

Aims

This study aimed to reveal the roles of TNNC1 in gastric cancer and the potential underlying mechanisms.

Methods

TNNC1 siRNAs and TNNC1 overexpression plasmid were used to alter its expression in AGS, MKN45, and HGC-27 cells. CCK-8 assay, colony formation, EdU assay, flow cytometry, transwell assay, and scratch test were conducted to measure the phenotype changes. In vivo effects of TNNC1 silence were confirmed by using a xenograft mouse model. Bioinformatics analysis was conducted to screen out the transcription factor and downstream signaling of TNNC1.

Results

TNNC1 was highly expressed in gastric cancer tissues and cell lines, and its expression was associated with poor prognosis. TNNC1 silence suppressed the proliferation, migration, and invasion of AGS and MKN45 cells. However, TNNC1 silence induced apoptosis by mediating the cleavage of caspase-3 and caspase-9. Overexpression of TNNC1 in HGC-27 cells led to the contrary effects. The anti-tumor effects of TNNC1 silence were also confirmed in a xenograft animal model. E2F1 was validated as an upstream transcription factor of TNNC1. Effects of TNNC1 silence on AGS cell migration and invasion were attenuated by E2F1 overexpression. Besides, TGF-β/Smad was a downstream signaling pathway of TNNC1. The anti-tumor impacts of TNNC1 silence were weaken by SB431542 (a specific inhibitor of TGF-β signaling) while accelerated by TGF-β.

Conclusion

TNNC1 activated by E2F1 functioned as an oncogenic gene through regulating TGF-β/Smad signaling. TNNC1 was suggested as a potential molecular drug target of gastric cancer.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Bucha S, Mukhopadhyay D, Bhattacharyya NP. E2F1 activates MFN2 expression by binding to the promoter and decreases mitochondrial fission and mitophagy in HeLa cells. FEBS J. 2019;286:4525–4541.

    Article  CAS  Google Scholar 

  2. Chung WK, Kitner C, Maron BJ. Novel frameshift mutation in Troponin C (TNNC1) associated with hypertrophic cardiomyopathy and sudden death. Cardiol Young. 2011;21:345–348.

    Article  Google Scholar 

  3. Deng JY, Liang H. Clinical significance of lymph node metastasis in gastric cancer. World J Gastroenterol. 2014;20:3967–3975.

    Article  Google Scholar 

  4. Digklia A, Wagner AD. Advanced gastric cancer: current treatment landscape and future perspectives. World J Gastroenterol. 2016;22:2403–2414.

    Article  CAS  Google Scholar 

  5. Engelmann D, Pützer BM. The dark side of E2F1: in transit beyond apoptosis. Cancer Res. 2012;72:571–575.

    Article  CAS  Google Scholar 

  6. Farra R, Dapas B, Grassi M, Benedetti F, Grassi G. E2F1 as a molecular drug target in ovarian cancer. Expert Opin Therap Targets. 2019;23:161–164.

    Article  CAS  Google Scholar 

  7. Hata A, Chen YG. TGF-β signaling from receptors to Smads. Cold Spring Harbor Perspect Biol. 2016;8:a022061.

    Article  Google Scholar 

  8. Hollern DP, Swiatnicki MR, Rennhack JP, Misek SA. E2F1 drives breast cancer metastasis by regulating the target gene FGF13 and altering cell migration. Sci Rep. 2019;9:10718.

    Article  Google Scholar 

  9. Jeong MH, Park SY, Lee SH, Seo J, Yoo JY, Park SH et al. EPB41L5 mediates TGFβ-induced metastasis of gastric cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2019;25:3617–3629.

    Article  CAS  Google Scholar 

  10. Jiang SX, Sheldrick M, Desbois A, Slinn J, Hou ST. Neuropilin-1 is a direct target of the transcription factor E2F1 during cerebral ischemia-induced neuronal death in vivo. Mol Cell Biol. 2007;27:1696–1705.

    Article  CAS  Google Scholar 

  11. Johnston JR, Chase PB, Pinto JR. Troponin through the looking-glass: emerging roles beyond regulation of striated muscle contraction. Oncotarget. 2018;9:1461–1482.

    Article  Google Scholar 

  12. Kim S, Kim J, Jung Y, Jun Y, Lee HY, Keum J et al. Characterization of TNNC1 as a novel tumor suppressor of lung adenocarcinoma. Mol Cells. 2020;43:619–631.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Leung CS, Yeung TL, Yip KP, Pradeep S, Balasubramanian L, Liu J et al. Calcium-dependent FAK/CREB/TNNC1 signalling mediates the effect of stromal MFAP5 on ovarian cancer metastatic potential. Nat Commun. 2014;5:5092.

    Article  CAS  Google Scholar 

  14. Li Y, Wang P, Ye D, Bai X, Zeng X, Zhao Q et al. IGHG1 induces EMT in gastric cancer cells by regulating TGF-β/SMAD3 signaling pathway. J Cancer. 2021;12:3458–3467.

    Article  CAS  Google Scholar 

  15. Li Z, Liu ZM, Xu BH. A meta-analysis of the effect of microRNA-34a on the progression and prognosis of gastric cancer. Eur Rev Med Pharmacol Sci. 2018;22:8281–8287.

    CAS  PubMed  Google Scholar 

  16. Ma F, Wang Z, Qiang Y, Xu L, Ding P, Wang Y et al. LukS-PV inhibits hepatocellular carcinoma cells migration via the TNNC1/PI3K/AKT Axis. OncoTargets Therapy. 2020;13:10221–10230.

    Article  CAS  Google Scholar 

  17. Martínez-Campos C, Torres-Poveda K, Camorlinga-Ponce M, Flores-Luna L, Maldonado-Bernal C, Madrid-Marina V et al. Polymorphisms in IL-10 and TGF-β gene promoter are associated with lower risk to gastric cancer in a Mexican population. BMC Cancer. 2019;19:453.

    Article  Google Scholar 

  18. Massip A, Arcondéguy T, Touriol C, Basset C, Prats H, Lacazette E. E2F1 activates p53 transcription through its distal site and participates in apoptosis induction in HPV-positive cells. FEBS Lett. 2013;587:3188–3194.

    Article  CAS  Google Scholar 

  19. Nadauld LD, Ford JM. Molecular profiling of gastric cancer: toward personalized cancer medicine. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31:838–839.

    Article  CAS  Google Scholar 

  20. Nomura A, Grove JS, Stemmermann GN, Severson RK. A prospective study of stomach cancer and its relation to diet, cigarettes, and alcohol consumption. Cancer Res. 1990;50:627–631.

    CAS  PubMed  Google Scholar 

  21. Pak KH, Park KC, Cheong JH. VEGF-C induced by TGF- β1 signaling in gastric cancer enhances tumor-induced lymphangiogenesis. BMC Cancer. 2019;19:799.

    Article  Google Scholar 

  22. Parvatiyar MS, Landstrom AP, Figueiredo-Freitas C, Potter JD, Ackerman MJ, Pinto JR. A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation. J Biol Chem. 2012;287:31845–31855.

    Article  CAS  Google Scholar 

  23. Ploski R, Rydzanicz M, Ksiazczyk TM, Franaszczyk M, Pollak A, Kosinska J et al. Evidence for troponin C (TNNC1) as a gene for autosomal recessive restrictive cardiomyopathy with fatal outcome in infancy. Am J Med Genet Part A. 2016;170:3241–3248.

    Article  CAS  Google Scholar 

  24. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.

    Article  Google Scholar 

  25. Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet (London, England). 2020;396:635–648.

    Article  CAS  Google Scholar 

  26. Song WJ, Van Keuren ML, Drabkin HA, Cypser JR, Gemmill RM, Kurnit DM. Assignment of the human slow twitch skeletal muscle/cardiac troponin C gene (TNNC1) to human chromosome 3p21.3→3p14.3 using somatic cell hybrids. Cytogenet Cell Genet. 1996;75:36–37.

    Article  CAS  Google Scholar 

  27. Tan Z. Recent advances in the surgical treatment of advanced gastric cancer: a review. Med Sci Monit Int Med J Exp Clin Res. 2019;25:3537–3541.

    Google Scholar 

  28. Venerito M, Link A, Rokkas T, Malfertheiner P. Review: Gastric cancer—clinical aspects. Helicobacter. 2019;24:e12643.

    PubMed  Google Scholar 

  29. Xie F, Ling L, van Dam H, Zhou F, Zhang L. TGF-β signaling in cancer metastasis. Acta Biochimica et Biophysica Sinica. 2018;50:121–132.

    Article  CAS  Google Scholar 

  30. Yang X, Wu K, Li S, Hu L, Han J, Zhu D et al. MFAP5 and TNNC1: Potential markers for predicting occult cervical lymphatic metastasis and prognosis in early stage tongue cancer. Oncotarget. 2017;8:2525–2535.

    Article  Google Scholar 

  31. Ye X, Xie G, Liu Z, Tang J, Cui M, Wang C et al. TNNC1 reduced gemcitabine sensitivity of nonsmall-cell lung cancer by increasing autophagy. Med Sci Monit Int Med J Exp Clin Res. 2020;26:e922703.

    CAS  Google Scholar 

  32. Yin JH, Elumalai P, Kim SY, Zhang SZ, Shin S, Lee M et al. TNNC1 knockout reverses metastatic potential of ovarian cancer cells by inactivating epithelial-mesenchymal transition and suppressing F-actin polymerization. Biochem Biophys Res Commun. 2021;547:44–51.

    Article  CAS  Google Scholar 

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Author notes

  1. Can Fang and Xinxin Zhang have contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Muping District, Yantai, 264100, Shandong, People’s Republic of China

    Can Fang, Xinxin Zhang, Fang Liu & Hui Liu

  2. Department of Digestive Endoscopy Room, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264100, Shandong, People’s Republic of China

    Chengyan Li

Authors
  1. Can Fang
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  2. Xinxin Zhang
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  4. Fang Liu
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  5. Hui Liu
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Contributions

XZ designed the study; CF and HL performed the research; CL and FL analyzed data; XZ wrote the paper.

Corresponding author

Correspondence to Hui Liu.

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The authors declare that they have no conflict of interest.

Ethics approval

The protocol of this research has been approved by the Ethics Committee of Yantai Affiliated Hospital of Binzhou Medical University. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

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Fang, C., Zhang, X., Li, C. et al. Troponin C-1 Activated by E2F1 Accelerates Gastric Cancer Progression via Regulating TGF-β/Smad Signaling. Dig Dis Sci 67, 4444–4457 (2022). https://doi.org/10.1007/s10620-021-07287-6

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  • DOI: https://doi.org/10.1007/s10620-021-07287-6

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