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Original Research

Open Access

Transcriptome sequencing reveals pathways and genes dysregulated in HPV infected cervical cancer

  • Qianxin Chen1
  • Jiajia Hu1
  • Xingwang Sun2
  • Wenbo Long2,*,

1Basic Medical College, Southwest Medical University, 646099 Sichuan, China

2Pathology Department of the First Affiliated Hospital, Southwest Medical University, 646099 Sichuan, China

DOI: 10.31083/j.ejgo.2020.06.5416 Vol.41,Issue 6,December 2020 pp.996-1003

Submitted: 05 November 2019 Accepted: 26 May 2020

Published: 15 December 2020

*Corresponding Author(s): Wenbo Long E-mail: wenbolong@swmu.edu.cn

Abstract

Objective: Cervical cancer is the fourth leading cause of cancer mortality in women worldwide. Cervical cancer is predominately caused by chronic infection with high-risk human papillomavirus (HR-HPV) genotypes. While several oncogenes and tumor suppressors are implicated in the initiation and progression of cervical cancer, the complicated genetic network regulating cancer is largely unknown. We aimed to study these oncogenes and tumor suppressors. Materials and methods: We extracted mRNA from paraffin-embedded tis-sues derived from cervical cancers infected with HPV-16, HPV-58, HPV-52, HPV-33 and HPV-35 and normal controls. Transcriptome sequencing was undertaken to analyze the differentially expressed genes (DEGs) between cancer and normal tissues. Results: Transcrip-tomic analysis screened 10,025 DEGs between cancerous and normal tissues (5,419 upregulated and 4606 downregulated). In KEGG analysis, most of the annotated DEGs were enriched in four sub-categories involved in MAPK, mTOR, PI3K-Akt, and Ras signaling pathways. And most of the key genes in these pathways were dysregulated at the mRNA level, including FGFR3, PDK2, PDK3, Akt1, Ras, MAPK1, MAPK3 and mTOR. The GO classification, KEGG enrichment and DEGs profiles of HPV-58 infected samples aligned closer to those of HPV-16 infected but were different from those of tissues infected with the other HPVs. Conclusions: These results suggest that the genesis of cervical cancer is associated with gene expression changes in specific cancer related signaling pathways. Thus, developing biomarkers and targets from these pathways may aide the diagnosis and targeted treatment of cervical cancers.

Keywords

Cervical cancer; Human papillomavirus; Transcriptome sequencing; Differentially expressed genes; Signaling pathway.


Cite and Share

Qianxin Chen,Jiajia Hu,Xingwang Sun,Wenbo Long. Transcriptome sequencing reveals pathways and genes dysregulated in HPV infected cervical cancer. European Journal of Gynaecological Oncology. 2020. 41(6);996-1003.

References

[1] Small W., Bacon M.A., Bajaj A., Chuang L.T., Fisher B.J., Harken-rider M.M., et al.: “Cervical cancer: A global health crisis”. Cancer, 2017, 123, 2404-2412.

[2] Boussios S., Seraj E., Zarkavelis G., Petrakis D., Kollas A., Kafan-tari A., et al.: “Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: Where do we stand? A literature review”. Crit. Rev. Oncol. Hematol., 2017, 108, 164-174.

[3] Seebacher N.A., Stacy A.E., Porter G.M., Merlot A.M.: “Clinical development of targeted and immune based anticancer therapies”. J. Exp. Clin. Cancer Res., 2019, 38, 156.

[4] Byron S.A., Van Keuren-Jensen K.R., Engelthaler D.M., Carpten J. D., Craig D.W.: “Translating RNA sequencing into clinical diagnostics: opportunities and challenges”. Nat. Rev. Genet., 2016, 17, 257-271.

[5] Chung W., Eum H.H., Lee H., Lee K., Lee H., Kim K., et al.: “Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer”. Nat. Commun., 2018, 8, 15081.

[6] Shukla S., Evans J.R., Malik R., Feng F.Y., Dhanasekaran S.M., Cao X., et al.: “Development of a RNA-Seq based prognostic signature in lung adenocarcinoma”. J. Natl. Cancer Inst., 2017, 109, djw200.

[7] Verma R., Sharma P.C.: “Next generation sequencing-based emerging trends in molecular biology of gastric cancer”. Am. J. Cancer Res., 2019, 8, 207-225.

[8] Bruni L., Diaz M., Castellsagué X., Ferrer E., Bosch F.X., de Sanjosé S.: “Cervical human papillomavirus prevalence in 5 continents: meta-analysis of 1 million women with normal cytological findings”. Int. J. Infect. Dis., 2010, 202, 1789-1799.

[9] Tang Y., Zheng L., Yang S., Li B., Su H., Zhang L.: “Epidemiology and genotype distribution of human papillomavirus (HPV) in Southwest China: a cross-sectional five years’ study in nonvaccinated women”. Virol. J., 2017, 14, 84.

[10] Mehta A.M., Mooij M., Branković I., Ouburg S., Morré S.A., Jordanova E.S.: “Cervical carcinogenesis and immune response gene polymorphisms: A review”. J. Immunol. Res., 2017, 2017, 8913860.

[11] Mocellin S., Tropea S., Benna C., Rossi C.R.: “Circadian pathway genetic variation and cancer risk: evidence from genome-wide association studies”. BMC Med., 2018, 16, 20.

[12] Hedegaard J., Thorsen K., Lund M.K., Hein A.K., Hamilton-Dutoit S. J., Vang S., et al.: “Next-generation sequencing of RNA and DNA isolated from paired fresh-frozen and formalin-fixed paraffin-embedded samples of human cancer and normal tissue”. PLoS One, 2015, 9, e98187.

[13] Xu P., Wang L., Huang L., Li W., Lv S., Lv M., et al.: “Identification and characterization of microRNAs expressed in human breast cancer chemo-resistant MCF-7/Adr cells by Solexa deep-sequencing technology”. Biomed. Pharmacother., 2015, 75, 173-178.

[14] Hoffman S.R., Le T., Lockhart A., Sanusi A., Dal Santo L., Davis M., et al.: “Patterns of persistent HPV infection after treatment for cervical intraepithelial neoplasia (CIN): A systematic review”. Int. J. Cancer, 2017, 14, 18-23.

[15] van de Putte G., Holm R., Lie A.K., Tropé C.G., Kristensen G.B.: “Expression of p27, p21, and p16 protein in early squamous cervical cancer and its relation to prognosis”. Gynecol. Oncol., 2003, 89, 140-147.

[16] Valenti G., Vitale S.G., Tropea A., Biondi A., Laganà A.S.: “Tumor markers of uterine cervical cancer: a new scenario to guide surgical practice?”. Updates Surg., 2018, 69, 441-449.

[17] Escobar-Hoyos L.F., Yang J., Zhu J., Cavallo J.A., Zhai H., Burke S., et al.: “Keratin 17 in premalignant and malignant squamous lesions of the cervix: proteomic discovery and immunohistochemical validation as a diagnostic and prognostic biomarker”. Mod. Pathol., 2014, 27, 621-630.

[18] Zhang L., Wu J., Ling M.T., Zhao L., Zhao K.: “The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses”. Mol. Cancer, 2015, 14, 87.

[19] Bahrami A., Hasanzadeh M., Hassanian S.M., ShahidSales S., Ghayour-Mobarhan M., Ferns G.A., et al.: “The potential value of the PI3K/Akt/mTOR Signaling pathway for assessing prognosis in cervical cancer and as a target for therapy”. J. Cell. Biochem., 2017, 118, 4163-4169.

[20] Lim H.J., Crowe P., Yang J.: “Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer”. J. Cancer Res. Clin. Oncol., 2015, 141, 671-689.

[21] Mahajan K., Mahajan N.P.: “PI3K-independent AKT activation in cancers: a treasure trove for novel therapeutics”. J. Cell. Physiol., 2012, 227, 3178-3184.

[22] Nitulescu G.M., Margina D., Juzenas P., Peng Q., Olaru O.T., Saloustros E., et al.: “Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review)”. Int. J. On-col., 2016, 48, 869-885.

[23] Parker J.A., Mattos C.: “The K-Ras, N-Ras, and H-Ras isoforms: Unique Conformational preferences and implications for targeting oncogenic mutants”. Cold Spring Harb. Perspect. Med., 2018, 8, a031427.

[24] Wegman P., Ahlin C., Sorbe B.: “Genetic alterations in the K-Ras gene influence the prognosis in patients with cervical cancer treated by radiotherapy”. Int. J. Gynecol. Cancer, 2011, 21, 86-91.

[25] Mammas I.N., Zafiropoulos A., Koumantakis E., Sifakis S., Span-didos D.A.: “Transcriptional activation of H- and N-ras oncogenes in human cervical cancer”. Gynecol. Oncol., 2004, 92, 941-948.

[26] Wee P., Wang Z.: “Epidermal growth factor receptor cell proliferation signaling pathways”. Cancers, 201, 9, 52.

[27] Germann U.A., Furey B.F., Markland W., Hoover R.R., Aronov A. M., Roix J.J., et al.: “Targeting the MAPK signaling path-way in cancer: promising preclinical activity with the novel selective ERK1/2 inhibitor BVD-523 (Ulixertinib)”. Mol. Cancer Ther., 2018, 16, 2351-2363.

[28] Aoki M., Fujishita T.: “Oncogenic roles of the PI3K/AKT/mTOR Axis”. Curr. Top. Microbiol. Immunol., 2019, 407, 153-189.

[29] Park J., Jung C.H., Seo M., Otto N.M., Grunwald D., Kim K.H., et al.: “The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14”. Autophagy, 2016, 12, 547-564.

[30] Babion I., Miok V., Jaspers A., Huseinovic A., Steenbergen R.D.M., van Wieringen W.N., et al.: “Identification of deregulated pathways, key regulators, and novel miRNA-mRNA interactions in HPV-mediated transformation”. Cancers, 2020, 12, 700.

[31] Long W., Yang Z., Li X., Chen M., Liu J., Zhang Y., et al.: “HPV-16, HPV-58, and HPV-33 are the most carcinogenic HPV genotypes in Southwestern China and their viral loads are associated with severity of premalignant lesions in the cervix”. Virol. J., 2018, 15, 94.


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