Aurora Kinase B in HPV-Driven Cervical Carcinogenesis: A Multifaceted Oncogenic Facilitator and Therapeutic Target

Transcriptional profiling analyses have revealed the upregulation of Aurora Kinase B (AURKB) in cervical squamous cell carcinoma and endocervical adenocarcinoma compared to normal epithelium (16). Recent studies using AURKB inhibitors in both in vitro and in vivo HPV-positive models have shown the suppression of key oncogenic drivers involved in cell proliferation, telomerase activity, and tumor formation, thereby establishing the therapeutic relevance of the HPV–AURKB interface as a promising target for molecular intervention. For a broader overview of related research, explore cutting-edge research in chemical biology and glycobiology .

Pharmacologic inhibition of AURKB has demonstrated significant anti-tumor effects in HPV-driven models:

These findings collectively demonstrate that AURKB activity is required for key malignant phenotypes in the HPV context. For more detailed insights into the therapeutic potential of targeting AURKB in HPV-driven cancers, refer to this research on AURKB inhibition in HPV-positive models .

The HPV-AURKB interaction is also involved in mechanisms of therapeutic resistance. Elevated AURKB expression has been associated with aggressive clinical behavior as well as reduced sensitivity to DNA-damaging agents in cervical cancer (CC) cell lines (85). AURKB expression can be induced by platinum agents such as cisplatin, and modulation of AURKB levels alters sensitivity to cisplatin and other chemotherapies in preclinical assays (86).

Another important concern is the potential contribution of AURKB signaling to CC stem cell biology and tumor dormancy, both of which are increasingly recognized as major determinants of recurrence and therapeutic resistance. Cervical cancer stem cell (CSC) populations characterized by stemness-associated phenotypes, including OCT4, SOX2, NANOG, CD44, and ALDH1 expression, possess enhanced tumor-initiating capacity and frequently demonstrate resistance to chemotherapy and radiotherapy, thereby contributing to disease relapse and poor clinical outcomes (87).

Aurora kinase signaling has been implicated in the maintenance of stemness and therapy-resistant cellular states across multiple malignancies. AURKA has been reported to regulate self-renewal pathways involving β-catenin and MYC signaling, while dysregulation of Aurora kinases broadly contributes to genomic plasticity and adaptation to therapeutic stress (88). Although direct evidence specifically linking AURKB to cervical CSC maintenance remains limited, AURKB-mediated regulation of chromosome segregation fidelity, spindle checkpoint control, and mitotic adaptation suggests plausible mechanisms through which persistent AURKB activation may facilitate the survival of therapy-tolerant cellular populations (69).

Residual tumor cells surviving initial therapy may enter reversible quiescent states and later contribute to recurrence following prolonged latency periods. Increasing evidence suggests that genomic instability, stress adaptation mechanisms, and checkpoint plasticity influence dormancy-associated therapeutic escape (89). Given the established role of AURKB in chromosomal stability and mitotic checkpoint regulation, determining whether AURKB signaling contributes directly to dormant tumor cell survival or recurrence-associated adaptation remains an unanswered question.

Molecularly, HPV E6 binds to AURKB via its C-terminal domain, influencing its phosphorylation state and activity. AURKB activation is tightly controlled through phosphorylation at multiple residues, such as Ser331 by Chk1 and Thr232 via INCENP interaction, which regulate its catalytic activity and centromeric localization. Phosphorylation of CENP-A at Ser7 by AURKA facilitates the recruitment of AURKB to centromeres, where this enzyme can further phosphorylate CENP-A at the same site. In HPV-positive CCs, phosphorylated AURKB levels are markedly elevated despite unchanged total protein levels (24). The silencing of E6 and E7 reduces both total and phosphorylated AURKB without affecting AURKB transcript levels, suggesting that HPV-driven AURKB activation is mediated through post-transcriptional mechanisms rather than gene overexpression (90).

Although AURKB overexpression strongly correlates with aggressive clinicopathological characteristics, chromosomal instability, and poor therapeutic outcomes in HPV-associated CC, current evidence suggests that AURKB primarily functions as a context-dependent oncogenic facilitator rather than an independent initiating driver of cervical carcinogenesis (27). Persistent high-risk HPV infection causes cervical transformation through E6- and E7-mediated disruption of p53 and pRb signaling pathways. In this context, AURKB dysregulation appears to emerge predominantly as a downstream consequence of HPV-mediated cellular reprogramming. However, AURKB contributes functionally to malignant progression by promoting mitotic checkpoint dysregulation, chromosome mis-segregation, cytokinetic failure, telomerase activation, and genomic instability, thereby amplifying oncogenic phenotypes initiated by viral transformation (52, 91, 92). Selective pharmacologic inhibition of AURKB reduces proliferation, impairs tumor growth, diminishes telomerase activity, and induces mitotic catastrophe in HPV-positive models, supporting a major role during tumor maintenance and progression rather than tumor initiation itself (93, 94).

Collectively, these studies highlight the multiple contributions of AURKB to HPV-mediated cervical oncogenesis. The direct molecular coupling of E6 and E7 to mitotic kinases, as well as the indirect pro-oncogenic consequences of viral disruption of cell cycle control, underscore the importance of AURKB both as a pathogenic effector and as a drug target in HPV-driven malignancies.

Persistent infection with HPV16 and HPV18 is a critical factor in cervical carcinogenesis, facilitating viral genome integration into the host DNA. This integration event disrupts the E2 regulatory gene, which normally represses E6 and E7 oncogenes. Loss of E2 function results in constitutive, deregulated expression of E6 and E7, further promoting oncogenic transformation by targeting tumor suppressors p53 and retinoblastoma protein (pRb) for degradation and inactivation, respectively (95, 96). Integration occurs preferentially at fragile sites within the host genome, including loci such as 3q28 and 8q24, and utilizes DNA damage repair pathways such as microhomology-mediated end joining (MMEJ) (3, 95). This generates genomic instability, chromosomal rearrangements, and epigenetic modifications, ultimately driving neoplastic CC progression.

Integration of HR-HPV DNA into the host genome is important for the transition from precancerous lesions to invasive cervical carcinoma. Multiple large-scale genomic and transcriptomic analyses have shown that the frequency of viral integration increases with lesion severity, being infrequent in low-grade lesions but highly prevalent in high-grade intraepithelial neoplasia and invasive cancers (97, 98). The insertion of HPV DNA frequently disrupts the viral E1 and E2 open reading frames, thereby abrogating transcriptional repression of E6 and E7 (99). The consequent overexpression of E6 and E7 oncoproteins sustains the degradation of p53 and pRb, driving genomic instability and proliferation (100). Jeon et al., 1995 have shown that HPV16 integration stabilizes E6/E7 mRNAs by removing AU-rich elements from the viral early 3′ untranslated region, which normally confer transcript instability (99). Warburton et al., 2018 used high-resolution genomic mapping and showed that HPV integration sites are frequently located near transcriptionally active chromatin domains, enhancers, or fragile regions, leading to virus–host chimeric transcripts, altered chromatin accessibility, and enhancer hijacking (101).