NRF2, p53, and p16: Predictive biomarkers to stratify human papillomavirus associated head and neck cancer patients for de-escalation of cancer therapy
Introduction
Human Papillomaviruses (HPV) is a family of closely related, epitheliotropic, non-enveloped double-stranded DNA viruses. HPV is the most widespread sexually transmitted infection, affecting both men and women globally (Weinstock et al., 2004; Koutsky, 1997; Cates, 1999; Hader et al., 2001). The clinical manifestation of the infection is influenced by several factors, including HPV type, anatomical site of infection, and host responses, and is classified as high-risk and low-risk subtypes based on the oncogenic potential. The high-risk subtype includes HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 (Munoz et al., 2003), which are responsible for almost all the cancers of the cervix and significant proportions of anogenital and head & neck cancers (Ljubojevic and Skerlev, 2014; Crow, 2012; Forman et al., 2012).
Beyond any doubt, HPV infection prominently HPV16 (accounts for 50 % cases) and HPV18 (accounts for 15 % cases), is linked with the development of virtually all-cervical cancer cases. Alarmingly, recent epidemiological evidence indicates a significant rise in HPV-driven Head and Neck Squamous Cell Carcinoma (HNSCC) (Gillison et al., 2015). HNSCC that comprises cancers of oral cavity, oropharynx, hypopharynx, and larynx, is the sixth leading malignancy with an estimated annual incidence of ∼633,000 and 355,000 deaths worldwide (Argiris et al., 2008). Historically the critical etiological factors associated with HNSCCs were tobacco use and heavy alcohol consumption (Gillison et al., 2008). In recent years, there has been a decline in the prevalence of HNSCC largely attributed to anti-smoking awareness programs and health policies (Dayyani et al., 2010). In contrast, there has been a gradual increase in the incidence of HNSCC, mainly oropharyngeal cancers, as a result of HPV infection (Ragin et al., 2007; Gillison, 2004; Gillison et al., 2000). This surge is so much that 25–50 % of HNSCC cases are estimated to be associated with HPV, and by 2020, it is projected that HPV attributed HNSCC will be more than cervical cancers in the United States of America (Chaturvedi et al., 2011). HPV in the Head & Neck region is sexually acquired and is relatively more prevalent among younger subjects having a higher number of sexual partners (Wierzbicka et al., 2013; D’souza et al., 2007). Evidence from pathological studies suggests that tumors of oropharynx, mostly base of the tongue and tonsillar area, are more frequently associated with HPV than those in the oral cavity and larynx (Combes and Franceschi, 2014; Ramqvist et al., 2015). The most striking feature between the HPV positive (HPV+ve) and HPV negative (HPV−ve) HNSCC patients is that HPV+ve HNSCC patient shows considerably better treatment response, higher survival rates and lower risks of recurrence as compared to HPV-ve HNSCC patients. This evidence has emphasized not only the need to diagnose and classify HPV+ve HNSCC as clinically and biologically distinct disease from HPV−ve HNSCC but also the urgent need to implement strategies and guidelines for de-escalation of treatment modalities (chemotherapy and radiotherapy) to reduce treatment-related morbidity and mortality. However, HPV infection alone cannot be a reliable marker for guiding the de-intensification of treatment modalities. There is an unmet need to develop sensitive, specific, and reliable biomarkers for guiding treatment modality. Understanding the pathogenic mechanisms in HPV+ve HNSCC and how HPV infection increases sensitivity to radio- and chemotherapy may help in developing reliable biomarkers for classifying HNSCC patients into ‘better responders’ versus ‘poor responders.' This review provides insights into unique molecular mechanisms and potential biomarkers underlying better prognosis associated with HPV+ve HNSCC.
The HPV virus has a double-stranded, circular DNA genome of 7900–8000 bp (Scheurer et al., 2005). The coding region encodes for two classes of genes: Early (E) genes [E1, E2, E4, E5, E6, and E7] and Late (L) genes [L1 and L2]. 'Early' genes regulate viral genome replication and cellular transformation, whereas 'Late' genes are involved in the assembly of viral particles. Upstream of the coding region is the upstream regulatory region, also referred to as an as long control region (LCR) which consists of an origin of replication, transcriptional enhancer and promoter sequences. The LCR region represents 10 % of the genome and varies substantially in nucleotide composition, leading to genetic heterogeneity among HPV subtypes (Fig. 1).
The HPV life cycle is tightly coupled with the proliferation and differentiation dynamics of host epithelial cells. The virus follows an interesting as well as a unique process of infection by restricting the productive life cycle to terminally differentiating squamous epithelial cells and thereby effectively evading the immune response. Upon contact with the epithelial cell, the major capsid protein L1 aids the virion to bind to heparan sulphate proteoglycans located on the surface of the cell and facilitates the viral entry (Doorbar et al., 2015). HPV is also known to bind to Cyclophilin B that increases L2 exposure and HPV uncoating (Sapp and Bienkowska-Haba, 2009; DiGiuseppe et al., 2015). The exposed L2 then binds to L2 specific receptor and Annexin A2 that allows viral internalization and endosomal escape. A secondary receptor α6β4 integrin is shown to enhance the internalization of virion via endocytosis (Aksoy et al., 2014; Abban and Meneses, 2010). The internalized virion is exposed to low pH conditions for several hours, leading to uncoating of the capsid proteins. The viral DNA is still bound to minor capsid protein L2, which mediates the transport of DNA along the cytoplasmic microtubules into the host nucleus (Bergant Marusic et al., 2012). The pre-requirement for the initiation of the viral life cycle is the maintenance of the viral genome in an episomal form (Thomas et al., 1999). The virus, once inside the basal epithelial cells, express E1 and E2 protein and recruits cellular replication machinery to maintain a low genome copy number (Burd, 2003). At the same time, E6 and E7 protein immortalize the infected cells by modulating cell cycle regulators. The maintenance phase though non-productive contributes to the evasion from the immune system and helps the virus to persist freely in the body. As the HPV infected cells leave the basal layer and start undergoing differentiation, there is an increased synthesis of viral proteins. In the suprabasal layer, E4 and E5 genes are expressed whose products favor the viral genome amplification and also increase the transformation activity of E6 & E7, leading to an increase in the viral genome copy number. At the same time, L1 and L2 genes are expressed to produce major and minor capsid proteins. Finally, in the granular layer, the capsid proteins gather along with the viral genome to assemble and form new virions. Research suggests that this compartmentalization of expressing genes at different times is the strategy employed by the virus to sustain long-term infection (Westrich et al., 2017). The viral genome replicates as an episome in infected cells; however, more often, the viral DNA is integrated into the host genome at random sites resulting in insertional mutagenesis, which may contribute to the development of preneoplastic lesions (McKinney et al., 2015; Zhao et al., 2016).
Although much of the knowledge related to carcinogenic mechanisms associated with HPV infection is derived from cervical cancer, the critical oncogenic mechanisms have also been validated in HNSCC. A large body of evidence from preclinical model systems and clinical studies indicate that the expression of viral E6 and E7 gene contributes to the malignant phenotype of HPV-associated cancers. Ectopic expression of E6 and E7 protein was sufficient to immortalize primary keratinocytes (Veldman et al., 2001). On the contrary, depletion of the E6 or E7 gene in HPV+ve HeLa cells inhibited proliferation and enhanced apoptosis. Likewise, the silencing of the HPV E6/E7 gene by shRNA in oropharyngeal squamous cell cancer cell lines inhibited proliferation and induced apoptosis (Adhim et al., 2013; Rampias et al., 2009).
As depicted in Fig. 2, E6 and E7 protein modulate multiple regulators involved in promoting the aberrant cell cycle and the malignant phenotype. Suppression or inactivation of tumor suppressor proteins, p53, and retinoblastoma (pRb), represent a prime oncogenic event promoted by E6 and E7 protein in the pathogenesis of HPV associated cancer. E6 protein interacts with p53 through E6-associated protein (E6-AP) and targets it to ubiquitination and proteasomal degradation in HPV-infected cells. As a result, p53 driven inhibition of cell cycle arrest and apoptosis is abolished in HPV-infected cells. Concomitantly, E7 protein interacts with tumor suppressor protein, retinoblastoma (pRb), and targets it to proteasomal degradation, which enables activation of transcription factor E2F leading to transcription of S-phase genes required for progression of the cell cycle. E7-directed pRb degradation also promotes overexpression of p16, and hence, elevated expression of p16 is considered as a surrogate marker of HPV infection (El-Naggar and Westra, 2012). In a transgenic mouse model, expression of E7 alone in cervical epithelium caused cervical dysplasia and cancer, and more importantly, repression of E7 expression by a tetracycline-regulated promoter caused regression of established cervical cancer (Riley et al., 2003). Similarly, disruption of the E7 gene by Zinc finger nuclease (Ding et al., 2014) or pharmacological repression of E7 expression by targeting CDK9 arrested proliferation of HPV+ve cervical cancer cell lines and inhibited the growth of tumor in xenograft model of cervical cancer. Collectively, these findings suggest that expression HPV E6 and E7 protein plays a prominent role in driving HPV associated cancer by switching off-tumor suppressor p53 and pRb.
Genomic alterations are widespread in HNSCC independent of HPV status. HPV+ve and HPV−ve cancers harbor amplifications and deletions on chromosome 3q, 5p, 8q, 3p, and 8p, respectively (Hayes et al., 2015; Walter et al., 2013). Genomic studies reported by Stransky et al. (2011), Agrawal et al. (2011), Pickering et al. (2013), and Seiwert et al. (2015) provided the molecular landscape of Head and Neck cancers. The Cancer Genome Atlas (TCGA) analyzed a total of 279 HNSCC cases (243 HPV−ve and 36 HPV+ve tumors) using multiple platforms such as DNA, RNA & miRNA sequencing and DNA methylation profiling and reported the most extensive mutational profile of HNSCC till date (Cancer Genome Atlas Network, 2015). Table 1 shows the frequency of mutated genes between HPV+ve and HPV−ve HNSCC, as reported by various studies.
As anticipated, the mutational frequency of the TP53 gene was markedly higher in HPV−ve tumors while it was rare or none in HPV+ve tumors. Similarly, the mutational frequency of EGFR, CDKN1A, and CDKN2A was markedly higher in HPV−ve tumors, whereas it was low to none in HPV+ve tumors. Another notable difference in the mutation profile between HPV+ve and HPV−ve tumors was noted in the regulators of oxidative stress response pathway- NFE2L2, KEAP1, and CUL3 genes. NFE2L2 (henceforth referred to as NRF2) is a transcriptional regulator of nearly all-cellular antioxidants. KEAP1 and CUL3 are negative regulators of NRF2 (details described in the subsequent sections). More than 1/3rd of HPV−ve HNSCC cases showed mutations in the NRF2 pathway (NFE2L2, KEAP1, and CUL3), while the frequency rate of the same genes in HPV+ve HNSCC was rare to none.
As summarized in Table 2, several clinical studies have observed better overall survival (60–80 %) of HPV+ve HNSCC patients as compared to stage-matched HPV−ve HNSCC patients after standard chemoradiotherapy. Furthermore, HPV status is an independent predictor of overall survival in patients with recurrent or metastatic HNSCC (Bossi et al., 2019; Deeken et al., 2015). In contrast, few studies have found that the overall survival of HPV+ve and HPV−ve HNSCC patients was similar when the anti-EGFR agent is added to standard chemotherapy, demonstrating no added benefits of EGFR inhibition (Su et al., 2018). However, in the same study, subgroup analysis showed a modest benefit in HPV−ve HNSCC patients, which could be related to a greater incidence of EGFR mutations in HPV−ve HNSCC patients (Table 1). To elucidate the underlying mechanisms for the better treatment response of HPV+ve HNSCC, many groups have performed comparative in vitro studies with HNSCC cell line panels with or without HPV. A study by Arenz et al. performed a radiation response in a panel of 8 HNSCC cell lines (4 HPV16+ve and 4 HPV−ve) originating from oropharynx, tongue, hypopharynx, and oral cavity. Their evaluation showed that HPV+ve cell lines were more radiosensitive than their counterparts. They also observed that HPV+ve cells accumulated more in the G2/M phase after irradiation and concluded that the enhanced sensitivity of HPV+ve cells could be due to impaired DNA double-strand break repair (Arenz et al., 2014). In a follow-up study, the same group reported that the basis for enhanced sensitivity of HPV+ve cancer cells to the combined treatment of irradiation and cisplatin could be related to dysregulation of cell cycle and increased apoptosis. In contrast, few studies have reported comparable sensitivity of HPV+ve and HPV−ve cancer cells to radiation (Nagel et al., 2013), cetuximab (Nagel et al., 2013), or cisplatin (Busch et al., 2016).
Section snippets
Unavailability of DNA damage repair (DDR) machinery and genomic instability in HPV+ve cancer cells
Cytotoxic effects of radiotherapy are primarily mediated by the accumulation of DNA double-strand breaks. Radio-sensitivity of cancer cells not only rely on the magnitude of DNA breaks inflicted by the ionizing radiation (Bakhoum et al., 2015), it also depends on pre-accumulated levels of chromosomal damage and DNA repair capacity. Cancer cells with reduced DNA repair capacity caused by the ablation of the ATM signal show increased sensitivity to ionizing radiation (Brenner et al., 2003). Drugs
A case for NRF2 pathway
Transcription factor NRF2 transcribes a broad spectrum of cellular antioxidant enzymes and detoxifying enzymes, which include but not limited to NQO1, GPX, TRX, GCLC, GCLM, HMOX1, and GR. In unstressed conditions, NRF2 is bound to adapter protein KEAP1 in the cytoplasm, which targets it to ubiquitination and proteasomal degradation through CUL3 dependent ubiquitin ligase. Upon exposures to ROS or electrophiles, KEAP1 undergoes conformational change culminating in the release and stabilization
Is it time for the de-intensification of treatment modalities for HPV positive HNSCC subjects?
Perhaps it may have been difficult to detect significant differences in the clinical outcomes between HPV and non-HPV associated cervical cancer because over 98 % of cervical cancer cases are associated with HPV infection. In contrast, HNSCC cases with or without HPV offered a better prospect to address the influence of HPV on clinical prognosis. As described in the above section, HPV+ve HNSCC patients show a better prognosis than HPV−ve HNSCC patients. Despite the better therapeutic responses,
Conclusion
The molecular pathogenesis and favorable therapeutic responses have demonstrated that HPV+ve tumors are clinically distinct from HPV−ve tumors. The accumulated evidence emphasizes the need for screening of HNSCC patients for HPV status and to de-escalate the treatment modalities for patients with HPV+ve HNSCC to avoid unwarranted toxicity. However, lack of reliable prognostic and predictive biomarkers other than HPV status has been a significant limitation in designing de-escalating therapy
Declaration of Competing Interest
None.
Acknowledgements
Rajesh K Thimmulappa (RKT) acknowledges the funding from Department of Biotechnology, Ramalingaswami Re-entry Fellowship, Government of India. Pushkal S Ramesh (PSR) acknowledges the award of Junior Research Fellowship from Council of Scientific and Industrial Research (CSIR), Government of India.
Pushkal S Ramesh is a doctoral student at the Center for Excellence in Molecular Biology & Regenerative Medicine, Department of Biochemistry, JSS Medical College, Mysuru. He is currently pursuing research on understanding the mechanism underlying better therapeutic responses of HPV associated Head & Neck Cancers. He has been awarded Junior Research Fellowship from Council of Scientific and Research (CSIR), Government of India. He is also a recipient of Young Scientist award and International
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2022, Archives of Oral BiologyCitation Excerpt :The clinico-pathological difference between the two head and neck cancer subsets is summarized in Table 1. Because of the distinct clinical features of HPV positive head and neck cancers, several clinical trials were initiated to de-escalate the current treatment paradigms to reduce the treatment related morbidity and mortality (Andreassen et al., 2018; Ramesh and Devegowda, et al., 2020; Ramesh & Krishnamurthy, 2020; Rosenberg and Vokes, 2021; Rühle et al., 2021). The earlier TNM staging did not include HPV positivity which posed problem for the clinicians.
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2021, Anais Brasileiros de DermatologiaCitation Excerpt :HPV testing is used, with restrictions, in patients at high risk for anal cancer: screening for the p16 protein by immunohistochemistry is recommended when moderate dysplasia or precancerous lesions are found.16 The identification of HPV in head and neck SCCs, by in situ hybridization or PCR, especially in tumors of the oropharynx (tonsil, base of tongue and soft palate) can be useful, as those associated with HPV have better therapeutic response, higher survival rates and lower risk of recurrence when compared to HPV-negative patients.16,20,21 Not all women with persistent HR HPV infection or precursor lesions in the cervix, even without treatment, will progress into cancer, suggesting that the identification of HR HPV alone does not define the evolution.15
Pushkal S Ramesh is a doctoral student at the Center for Excellence in Molecular Biology & Regenerative Medicine, Department of Biochemistry, JSS Medical College, Mysuru. He is currently pursuing research on understanding the mechanism underlying better therapeutic responses of HPV associated Head & Neck Cancers. He has been awarded Junior Research Fellowship from Council of Scientific and Research (CSIR), Government of India. He is also a recipient of Young Scientist award and International Travel support from Department of Biotechnology, Science & Engineering Research Board (DST-SERB), Government of India for attending 32nd International Papillomavirus Conference (IPVC), held on October 2–6, 2018 in Sydney, Australia.
Devananda Devegowda is an Assistant Professor at Center for Excellence in Molecular Biology & Regenerative Medicine, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research Mysuru. He has over a decade of experience in diagnostic developments using PCR, hybridoma and immunological based approaches for infectious and inflammatory diseases and currently his laboratory is working on HPV based cancers including burden of HPV associated cancers, understanding the mechanism of carcinogenesis and better therapeutic responses in HPV associated Head & Neck Cancers.
Anju Singh is an Assistant Scientist at Bloomberg School of Public Health, Johns Hopkins University, Baltimore. Her early research led to discovery of aberrant Nrf2-Keap1 signal in lung cancer. Subsequently, her research spanning over 15 year have elucidated the role of transcription factor Nrf2 in regulation of cellular antioxidants and metabolism and its implication in tumorigenesis, radioresistance and chemoresistance. Her current research is focused on discovering and developing pharmacological inhibitors of NRF2 for cancer treatment.
Rajesh Thimmulappa is an Associate Professor at Center for Excellence in Molecular Biology & Regenerative Medicine Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru. His research spanning over 20yr with over 50 publications have explored the molecular role of NRF2 in mounting adaptive stress responses (incudes nearly all cellular antioxidants) against diverse environmental stressors (tobacco smoke, air pollutant, microbes, radiation) to mitigate oxidative stress and inflammation. His research has demonstrated NRF2 as drug target for prevention and treatment of diverse inflammatory diseases and cancer.