Skip to main content

Advertisement

Log in

HOXC13 promotes cervical cancer proliferation, invasion and Warburg effect through β-catenin/c-Myc signaling pathway

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

Cervical cancer (CC) is one of the most common malignancy and is the second leading cause of death in gynecologic malignancies worldwide. The homeobox transcription factor homeobox C13 (HOXC13) has been demonstrated to play crucial roles in various cancers. However, its function in CC remains to be addressed. In the present study, upregulation of HOXC13 expression in human CC tissues was found in The Cancer Genome Atlas (TCGA) dataset and clinical samples and was associated with tumor size, FIGO stage and lymph node metastasis. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assays suggested that the expression of HOXC13 was up-regulated in CC cells. Cell Counting Kit (CCK)-8, colony formation and cell cycle analysis assays indicated that HOXC13 promoted the proliferation and cycle progression of CC cells in vitro. Of note, knockdown of HOXC13 hinders tumor growth of xenograft tumor mice in vivo. Moreover, transwell and glycolysis measurement assays demonstrated that HOXC13 enhanced the migration, invasion and glycolysis of CC cells in vitro. Further mechanism analysis suggested that HOXC13 participated in CC progression through regulation of the β-catenin/c-Myc signaling pathway. Collectively, HOXC13 facilitated cell proliferation, migration, invasion and glycolysis through modulating β-catenin/c-Myc signaling pathway in CC, indicating that HOXC13 may provide a promising therapeutic target for the therapy of CC.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article.

Code availability

Not Applicable.

References

  • Bhatlekar S, Fields JZ, Boman BM (2014) HOX genes and their role in the development of human cancers. J Mol Med 92(8):811–823

    Article  CAS  Google Scholar 

  • Bhatlekar S, Fields JZ, Boman BM (2018) Role of HOX genes in stem cell differentiation and cancer. Stem Cells Int 2018:3569493

    Article  Google Scholar 

  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424

    Article  Google Scholar 

  • Derks M, van der Velden J, de Kroon CD, Nijman HW, van Lonkhuijzen LRCW, van der Zee AGJ, Zwinderman AH, Kenter GG (2018) Surgical treatment of early-stage cervical cancer: a multi-institution experience in 2124 cases in the Netherlands over a 30-year period. Int J Gynecol Cancer 28(4):757

    Article  Google Scholar 

  • Fuentealba LC, Eivers E, Ikeda A, Hurtado C, Kuroda H, Pera EM, De Robertis EM (2007) Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell 131(5):980–993

    Article  CAS  Google Scholar 

  • Gordon J (2018) Hox genes in the pharyngeal region: How Hoxa3 controls early embryonic development of the pharyngeal organs. Int J Dev Biol 62(11–12):775–783

    Article  CAS  Google Scholar 

  • Gupta A, Ajith A, Singh S, Panday RK, Samaiya A, Shukla S (2018) PAK2–c-Myc–PKM2 axis plays an essential role in head and neck oncogenesis via regulating Warburg effect. Cell Death Dis 9(8):825

    Article  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  Google Scholar 

  • Hasanpourghadi M, YengLooi C, Kumar Pandurangan A, Sethi G, Fen Wong W, Rais Mustafa M (2017) Phytometabolites targeting the Warburg effect in cancer cells: a mechanistic review. J Curr Drug Targets 18(9):1086–1094

    CAS  Google Scholar 

  • Hsieh AL, Walton ZE, Altman BJ, Stine ZE, Dang CV (2015) MYC and metabolism on the path to cancer. Semin Cell Dev Biol 43:11–21

    Article  CAS  Google Scholar 

  • Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S, Hild M, Shi X, Wilson CJ, Mickanin C, Myer V, Fazal A, Tomlinson R, Serluca F, Shao W, Cheng H, Shultz M, Rau C, Schirle M, Schlegl J, Ghidelli S, Fawell S, Lu C, Curtis D, Kirschner MW, Lengauer C, Finan PM, Tallarico JA, Bouwmeester T, Porter JA, Bauer A, Cong F (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461(7264):614–620

    Article  CAS  Google Scholar 

  • Ishii Y, Taguchi A, Kukimoto I (2020) The homeobox transcription factor HOXC13 upregulates human papillomavirus E1 gene expression and contributes to viral genome maintenance. FEBS Lett 594(4):751–762

    Article  CAS  Google Scholar 

  • Kasiri S, Ansari KI, Hussain I, Bhan A, Mandal SS (2013) Antisense oligonucleotide mediated knockdown of HOXC13 affects cell growth and induces apoptosis in tumor cells and over expression of HOXC13 induces 3D-colony formation. J RSC Adv 3(10):3260–3269

    Article  CAS  Google Scholar 

  • Kim J-w, Gao P Liu, Y-C, Semenza GL, Dang CV (2007) HIF-1 and dysregulated c-Myc cooperatively induces VEGF and metabolic switches, HK2 and PDK1. J Mol Cell Biol

  • Kobayashi Y, Banno K, Kunitomi H, Takahashi T, Takeda T, Nakamura K, Tsuji K, Tominaga E, Aoki D (2019) Warburg effect in gynecologic cancers. J Obstet Gynaecol Res 45(3):542–548

    Article  Google Scholar 

  • Koppenol WH, Bounds PL, Dang CV (2011) Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer 11(5):325–337

    Article  CAS  Google Scholar 

  • Li C, Cui J, Zou L, Zhu L, Wei W (2020) Bioinformatics analysis of the expression of HOXC13 and its role in the prognosis of breast cancer. J Oncol Lett 19(1):899–907

    CAS  Google Scholar 

  • Li L, Wang Y, Song G, Zhang X, Gao S, Liu H (2019) HOX cluster-embedded antisense long non-coding RNAs in lung cancer. Cancer Lett 450:14–21

    Article  CAS  Google Scholar 

  • Li W, Zhu Q, Zhang S, Liu L, Zhang H, Zhu D (2020) HOXC13-AS accelerates cell proliferation and migration in oral squamous cell carcinoma via miR-378g/HOXC13 axis. Oral Oncol 111:104946

    Article  CAS  Google Scholar 

  • Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 41(3):211–218

    Article  CAS  Google Scholar 

  • Liu F, Chen Y, Zhu G, Hysi PG, Wu S, Adhikari K, Breslin K, Pośpiech E, Hamer MA, Peng F, Muralidharan C, Acuna-Alonzo V, Canizales-Quinteros S, Bedoya G, Gallo C, Poletti G, Rothhammer F, Bortolini MC, Gonzalez-Jose R, Zeng C, Xu S, Jin L, Uitterlinden AG, Ikram MA, van Duijn CM, Nijsten T, Walsh S, Branicki W, Wang S, Ruiz-Linares A, Spector TD, Martin NG, Medland SE, Kayser M (2018) Meta-analysis of genome-wide association studies identifies 8 novel loci involved in shape variation of human head hair. Hum Mol Genet 27(3):559–575

    Article  CAS  Google Scholar 

  • Luo J, Wang Z, Huang J, Yao Y, Sun Q, Wang J, Shen Y, Xu L, Ren B (2018) HOXC13 promotes proliferation of esophageal squamous cell carcinoma via repressing transcription of CASP3. Cancer Sci 109(2):317–329

    Article  CAS  Google Scholar 

  • Luo Z, Rhie SK, Farnham PJJC (2019) The enigmatic HOX genes: can we crack their code? Cancers 11(3):323

    Article  CAS  Google Scholar 

  • Mallo M (2020) The vertebrate tail: a gene playground for evolution. Cell Mol Life Sci 77(6):1021–1030

    Article  CAS  Google Scholar 

  • Meijer CJLM, Snijders PJF (2014) Screening comes of age and treatment progress continues. Nat Rev Clin Oncol 11(2):77–78

    Article  CAS  Google Scholar 

  • Meng H, Liu J, Qiu J, Nie S, Jiang Y, Wan Y, Cheng W (2020) Identification of key genes in association with progression and prognosis in cervical squamous cell carcinoma. DNA Cell Biol 39(5):848–863

    Article  CAS  Google Scholar 

  • Miller DM, Thomas SD, Islam A, Muench D, Sedoris K (2012) c-Myc and cancer metabolism. Clin Cancer Res 18(20):5546

    Article  CAS  Google Scholar 

  • Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, Xu Y, Wonsey D, Lee LA, Dang CV (2000) Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem 275(29):21797–21800

    Article  CAS  Google Scholar 

  • Reynoso-Noverón N, Peña-Nieves A, Rodríguez MO, Mohar-Betancourt A (2017) Cervical cancer epidemiology. In Cervical cancer. Springer, pp 19–33

  • Shim H, Dolde C, Lewis BC, Wu C-S, Dang G, Jungmann RA, Dalla-Favera R, Dang CV (1997) c-Myc transactivation of LDH-A: Implications for tumor metabolism and growth. Proc Natl Acad Sci U S A 94(13):6658–6663

    Article  CAS  Google Scholar 

  • Shrestha AD, Neupane D, Vedsted P, Kallestrup P (2018) Cervical cancer prevalence, incidence and mortality in low and Middle Income Countries: a systematic review. Asian Pac J Cancer Prev 19(2):319–324

    PubMed  PubMed Central  Google Scholar 

  • Small W Jr, Bacon MA, Bajaj A, Chuang LT, Fisher BJ, Harkenrider MM, Jhingran A, Kitchener HC, Mileshkin LR, Viswanathan AN (2017) Cervical cancer: a global health crisis. J Cancer 123(13):2404–2412

    Article  Google Scholar 

  • Svingen T, Tonissen KF (2003) Altered HOX gene expression in human skin and breast cancer cells. Cancer Biol Ther 2(5):518–523

    Article  CAS  Google Scholar 

  • Turcotte M, Abadi A, Peralta-Romero J, Suarez F, Reddon H, Gomez-Zamudio J, Burguete-Garcia AI, Cruz M, Meyre D (2019) Genetic contribution to waist-to-hip ratio in Mexican children and adolescents based on 12 loci validated in European adults. Int J Obes 43(1):13–22

    Article  Google Scholar 

  • Vander Heiden MG (2011) Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 10(9):671–684

    Article  CAS  Google Scholar 

  • Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8(6):519–530

    Article  CAS  Google Scholar 

  • Wu Y, Wang A, Zhu B, Huang J, Lu E, Xu H, Xia W, Dong G, Jiang F, Xu L (2018) KIF18B promotes tumor progression through activating the Wnt/β-catenin pathway in cervical cancer. Onco Targets Ther 11:1707–1720

    Article  Google Scholar 

  • Yao Y, Luo J, Sun Q, Xu T, Sun S, Chen M, Lin X, Qian Q, Zhang Y, Cao L, Zhang P, Lin Y (2017) HOXC13 promotes proliferation of lung adenocarcinoma via modulation of CCND1 and CCNE1. Am J Cancer Res 7(9):1820–1834

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

MMD and LS designed the study, supervised the data collection, analyzed the data,

JJS and LYW interpreted the data and prepared the manuscript for publication, KNZ supervised the data collection, analyzed the data and reviewed the draft of the manuscript. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Li Shu.

Ethics declarations

Ethics approval

All experiments in this study were approved by the Animal Care and Use Committee of the 2nd Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University and performed in accordance with the Guide for the Care and Use of Laboratory Animals.

Consent to participate

Not Applicable.

Consent for publication

Written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article.

Competing interests

The authors state that there are no conflicts of interest to disclose.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dai, M., Song, J., Wang, L. et al. HOXC13 promotes cervical cancer proliferation, invasion and Warburg effect through β-catenin/c-Myc signaling pathway. J Bioenerg Biomembr 53, 597–608 (2021). https://doi.org/10.1007/s10863-021-09908-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-021-09908-1

Keywords

Navigation