Recombinant Viral Capsid Protein L2 (rVL2) of HPV 16 Suppresses Cell Proliferation and Glucose Metabolism via ITGB7/C/EBPβ Signaling Pathway in Cervical Cancer Cell Lines

Purpose Capsid protein L2 is the minor capsid protein of human papillomavirus 16 (HPV16). Although L2-based vaccines were developed, the therapeutic effect of recombinant viral capsid protein L2 (rVL2) was still to be illustrated. Methods We used glucose uptake and lactate production assay to verify the inhibitory effect of rVL2 on the glucose metabolism in cervical cancer cells. Secondly, we performed gene-chip assay, RT-PCR, and Western blot to determine the role of ITGB7/C/EBPβ signaling pathway in rVL2-mediated glucose metabolism in vitro. Finally, we used an animal model to verify the function of rVL2 in cervical cancer. Results We found that rVL2 reduced glucose uptake and lactate production levels in cervical cancer cells, which caused the inhibition of cell proliferation. rVL2 decreased the expression levels of key metabolic enzymes, including GLUT1, LDHA, and ALDOA, to affect cell metabolism in cervical cancer cells by inhibiting ITGB7/C/EBPβ signaling pathway in vitro and in vivo. Conclusion These results demonstrated the vital role of rVL2 in the glycolysis-induced cell growth and proliferation via suppressing ITGB7/C/EBPβ signaling axis.

[1]  S. Do,et al.  Role of integrin β1 as a biomarker of stemness in head and neck squamous cell carcinoma. , 2019, Oral oncology.

[2]  Meng Li,et al.  ITGB4 is a novel prognostic factor in colon cancer , 2019, Journal of Cancer.

[3]  E. Wang,et al.  Glucose Transporter 1 Promotes the Malignant Phenotype of Non-Small Cell Lung Cancer through Integrin β1/Src/FAK Signaling , 2019, Journal of Cancer.

[4]  Beibei Chen,et al.  Correlation of integrin alpha 7 with clinicopathological characteristics and survival profiles, as well as its regulatory role in cell proliferation, apoptosis, and stemness in non‐small‐cell lung cancer , 2019, Journal of clinical laboratory analysis.

[5]  Jae U. Jung,et al.  Efficient Inhibition of Human Papillomavirus Infection by L2 Minor Capsid-Derived Lipopeptide , 2019, mBio.

[6]  C. Hong,et al.  Enhancing prognosis prediction using pre-treatment nodal SUVmax and HPV status in cervical squamous cell carcinoma , 2019, Cancer Imaging.

[7]  Probal Banerjee,et al.  Dietary Polyphenols, Resveratrol and Pterostilbene Exhibit Antitumor Activity on an HPV E6-Positive Cervical Cancer Model: An in vitro and in vivo Analysis , 2019, Front. Oncol..

[8]  L. Kong,et al.  CCAAT/Enhancer Binding Protein β-Mediated MMP3 Upregulation Promotes Esophageal Squamous Cell Cancer Invasion In Vitro and Is Associated with Metastasis in Human Patients. , 2019, Genetic testing and molecular biomarkers.

[9]  K. Palmer,et al.  Vaccine synergy with virus-like particle and immune complex platforms for delivery of human papillomavirus L2 antigen. , 2019, Vaccine.

[10]  M. Liro,et al.  New therapeutic approaches in the treatment of node-positive cervical cancer patients based on molecular targets: a systematic review. , 2019, Ginekologia polska.

[11]  Fei Liu,et al.  Cryptotanshinone suppresses cell proliferation and glucose metabolism via STAT3/SIRT3 signaling pathway in ovarian cancer cells , 2018, Cancer medicine.

[12]  Xianghuo He,et al.  Programmed death ligand 1 promotes lymph node metastasis and glucose metabolism in cervical cancer by activating integrin β4/SNAI1/SIRT3 signaling pathway , 2018, Oncogene.

[13]  S. K. Campos.  Subcellular Trafficking of the Papillomavirus Genome during Initial Infection: The Remarkable Abilities of Minor Capsid Protein L2 , 2017, Viruses.

[14]  M. Sapp,et al.  Cruising the cellular highways: How human papillomavirus travels from the surface to the nucleus. , 2017, Virus research.

[15]  L. Xuan,et al.  Resistance to chemotherapy is associated with altered glucose metabolism in acute myeloid leukemia. , 2016, Oncology letters.

[16]  Dario R. Roque,et al.  Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling. , 2015, Gynecologic oncology.

[17]  Junfeng Zhang,et al.  C/EBP-β-activated microRNA-223 promotes tumour growth through targeting RASA1 in human colorectal cancer , 2015, British Journal of Cancer.

[18]  Gong Yang,et al.  Fibrillin-1, induced by Aurora-A but inhibited by BRCA2, promotes ovarian cancer metastasis , 2015, Oncotarget.

[19]  Lucas Pelkmans,et al.  Large Scale RNAi Reveals the Requirement of Nuclear Envelope Breakdown for Nuclear Import of Human Papillomaviruses , 2014, PLoS pathogens.

[20]  R. Roden,et al.  L2, the minor capsid protein of papillomavirus. , 2013, Virology.

[21]  Gilles A. Spoden,et al.  Host-cell factors involved in papillomavirus entry , 2012, Medical Microbiology and Immunology.

[22]  Jei-Ming Peng,et al.  Recombinant viral capsid protein VP1 suppresses migration and invasion of human cervical cancer by modulating phosphorylated prohibitin in lipid rafts. , 2012, Cancer letters.

[23]  Y. Qiao,et al.  A cross-sectional study on the acceptability of self-collection for HPV testing among women in rural China , 2012, Sexually Transmitted Infections.

[24]  Jei-Ming Peng,et al.  Recombinant viral protein promotes apoptosis and suppresses invasion of ovarian adenocarcinoma cells by targeting α5β1 integrin to down‐regulate Akt and MMP‐2 , 2012, British journal of pharmacology.

[25]  S. Liang,et al.  Recombinant VP1, an Akt Inhibitor, Suppresses Progression of Hepatocellular Carcinoma by Inducing Apoptosis and Modulation of CCL2 Production , 2011, PloS one.

[26]  P. Tassone,et al.  Integrin β7-mediated regulation of multiple myeloma cell adhesion, migration, and invasion. , 2011, Blood.

[27]  R. Chatterjee,et al.  CpG methylation of half-CRE sequences creates C/EBPα binding sites that activate some tissue-specific genes , 2010, Proceedings of the National Academy of Sciences.

[28]  M. Sapp,et al.  Viral entry mechanisms: human papillomavirus and a long journey from extracellular matrix to the nucleus , 2009, The FEBS journal.

[29]  Myoung H. Kim,et al.  Translationally regulated C/EBPβ isoform expression upregulates metastatic genes in hormone‐independent prostate cancer cells , 2008, The Prostate.

[30]  B. Trus,et al.  Arrangement of L2 within the Papillomavirus Capsid , 2008, Journal of Virology.

[31]  Y. Modis,et al.  Atomic model of the papillomavirus capsid , 2002, The EMBO journal.

[32]  Arnoud Sonnenberg,et al.  Function and interactions of integrins , 2001, Cell and Tissue Research.

[33]  P. Kluin,et al.  Preferential expression of the mucosal homing receptor integrin alpha 4 beta 7 in gastrointestinal non-Hodgkin's lymphomas. , 1997, The American journal of pathology.

[34]  H. zur Hausen,et al.  Papillomavirus infections--a major cause of human cancers. , 1996, Biochimica et biophysica acta.

[35]  E. Butcher,et al.  L-selectin and alpha 4 beta 7 integrin homing receptor pathways mediate peripheral lymphocyte traffic to AKR mouse hyperplastic thymus. , 1995, The American journal of pathology.

[36]  S. Pals,et al.  Expression of the mucosal homing receptor α4β7 in malignant lymphomatous polyposis of the intestine , 1994 .

[37]  S. Pals,et al.  Expression of the mucosal homing receptor alpha 4 beta 7 in malignant lymphomatous polyposis of the intestine. , 1994, Gastroenterology.

[38]  Y. Oshika,et al.  P-glycoprotein-mediated acquired multidrug resistance of human lung cancer cells in vivo. , 1996, British Journal of Cancer.