Kadambari Suri

Background: Though prophylactic vaccines exist, ~80% of people (both men and women) will be infected by human papillomavirus (HPV) during their lifetime. While outcomes of HPV infection vary significantly among individuals, HPV is responsible for about one-third of all cancers – including the majority of cases of cervical cancer, the fourth most common cancer among women.^1,2  Primarily transmitted via sexual contact, HPV infects the basal layer of squamous epithelium resulting in the viral genomes being persistently maintained as a low-copy number in the episomal form. On a molecular level, human papillomavirus binds heparan sulfate proteoglycans, side chains of syndecan-1 heparan sulphate, in the extracellular matrix (ECM). Enzymes like heparanase-1 cleave heparan sulphate side chains and release HPV from infected cells, leading to potential increase of malignancy.³  Prophylactic HPV vaccines are impotent against pre-existing HPV-related pre-cancerous and cancerous alterations. Thus, the impact of HPV as a cancer-causing agent is staggering.⁴

Objective(s):  A therapeutic agent able to inhibit HPV at various stages of infection may significantly improve the treatment for cervical cancer. Direct and indirect heparan sulfate proteoglycan may be promising therapeutics against HPV.

Search Methods:  An online search of the PubMed database between 2017 to 2023 was conducted using the following keywords: “Human Papillomavirus,” “heparan sulfate [proteoglycans],” therapeutics

Results:  Studies have established the critical role of heparan sulfate proteoglycan at various stages of HPV lifecycle from initial infection to malignancy. To highlight a few – p63 is found to regulate HPV infection by targeting protein syndecan-1, the most abundant heparan sulfate proteoglycan and the primary HPV attachment receptor, via DNp63-bound super-enhancers.³ Moreover, heparinase is shown to be highly expressed in cervical cancers – specifically promoting cell proliferation via the NF- κB signaling pathway.⁵  The underlying mechanism of the progression of HPV to malignancy (i.e., cervical cancer) suggests that heparan sulfate plays a crucial role and, therefore, poses as a promising target for therapeutic agents. Studies have shown that heparin-neutralizing agents, such as protamine sulfate, can improve treatment at various stages of HPV infection. Although protamine sulfate is still being investigated for clinical development (i.e., clinical trials), limitations of studies have demonstrated limited applications of protamine sulfate as a broad-spectrum topical microbicide for the genital tract.⁶ To assess the potential for a universal solution, heparin-like molecules, such as 3,6-O-sulfated chitosan, show success while cautioning off-target effects.⁷ More mechanism-based inhibitors – specifically against cancer metastasis, have comparable efficacy to current cancer treatments though they prove tedious.⁸

Conclusion:  Heparan sulfate targets have provided promising preliminary results. Given the findings, the following should be explored: 1) mechanistic therapeutics and 2) directly targeting heparan sulfate proteoglycans to minimize off-target effects and maximize on-target effects. Further research into, and implementation of, pharmaceutical therapies may be lifesaving.

Works Cited

1. Gupta S, Kumar P, Das BC. HPV: Molecular pathways and targets.Curr Probl Cancer. 2018;42(2):161-174. doi:10.1016/j.currproblcancer.2018.03.003
2. Szymonowicz KA, Chen J. Biological and clinical aspects of HPV-related cancers.Cancer Biol Med. 2020;17(4):864-878. doi:10.20892/j.issn.2095-3941.2020.0370
3. Glathar AR, Oyelakin A, Gluck C, Bard J, Sinha S. p63 Directs Subtype-Specific Gene Expression in HPV+ Head and Neck Squamous Cell Carcinoma.Front Oncol. 2022;12:879054. Published 2022 May 31. doi:10.3389/fonc.2022.879054
4. Khairkhah N, Bolhassani A, Najafipour R. Current and future direction in treatment of HPV-related cervical disease.J Mol Med (Berl). 2022;100(6):829-845. doi:10.1007/s00109-022-02199-y
5. Lv Q, Wu K, Liu F, Wu W, Chen Y, Zhang W. Interleukin‑17A and heparanase promote angiogenesis and cell proliferation and invasion in cervical cancer.Int J Oncol. 2018;53(4):1809-1817. doi:10.3892/ijo.2018.4503z
6. Young JM, Zine El Abidine A, Gómez-Martinez RA, et al. Protamine Sulfate Is a Potent Inhibitor of Human Papillomavirus InfectionIn Vitro and In Vivo. Antimicrob Agents Chemother. 2022;66(1):e0151321. doi:10.1128/AAC.01513-21
7. Gao Y, Liu W, Wang W, Zhang X, Zhao X. The inhibitory effects and mechanisms of 3,6-O-sulfated chitosan against human papillomavirus infection.Carbohydr Polym. 2018;198:329-338. doi:10.1016/j.carbpol.2018.06.096
8. de Boer C, Armstrong Z, Lit VAJ, et al. Mechanism-based heparanase inhibitors reduce cancer metastasis in vivo.Proc Natl Acad Sci U S A. 2022;119(31):e2203167119. doi:10.1073/pnas.2203167119