The results of this study provide important insights into the differential expression of normally downregulated oncomirs (miR-21, miR-146a, miR-155, miR-182, and miR-200c) and normally upregulated tumour suppressors (miR-let-7b, miR-125b, miR-143, miR-145, and p53 expression) and their potential roles in HIV-related cervical carcinogenesis. The findings have significant implications for understanding the molecular mechanisms underlying cervical cancer risk. Since an earlier study demonstrated that miR-143, miR-145, miR-146a and miR-182 play direct roles in immunological processes [7], this study evaluates the potential utility of these miRNAs as predictive biomarkers for cervical cancer risk assessment and their suitability as therapeutic targets.
The differential expression of miR-21 and miR-155 is particularly intriguing. Both miR-21 and miR-155 are often associated with promoting cell proliferation, inhibiting apoptosis, and enhancing cell survival—hallmark features of cancer. Their higher expression in cervical cells of HIV + women may indicate vulnerability to cervical cancer development. However, it is essential to consider that the functions of miRNAs can be context-dependent, influenced by various factors including target genes and cellular conditions. The study carried out by Gokavi et al. revealed that the inhibition of miR-155 forestalls HIV release in the infected cervical epithelial cell line (ME-180) through the upregulated TGF-β signaling [8]. Bazie et al. opined that elevated miR-155 in plasma large and small extracellular vesicles promotes immune activation and increases the risk of morbidity and mortality among people living with HIV, irrespective of viral replication or antiretroviral therapy status [9]. An experimental study carried out Li et al. revealed that HIV-infected T-cells secrete exosomal miR-155-5p which in turn promotes the proliferation, migration, and invasion of cervical cancer cells through IL-6 and IL-8 activation [10]. Taken together, this study suggests that the elevated levels of miR-155 in HIV + women drive malignant epithelial transformation through an HIV-release-associated inflammatory mechanism [11]. The pro-inflammatory effect of the elevated levels of miRNA-155 in HIV + women appears to be countered by corresponding elevated levels of p53 [12,13].
Higher levels of tumour-suppressive p53 and miR-let-7b in cervical cells were evident in cervical cells from HIV + women. The elevated expressions of the miRNAs in cervical cells of HIV + women suggest a potential protective mechanism against cervical carcinogenesis. Apart from being anti-inflammatory, miR-let-7b targets oncogenes and inhibits cell growth [12]. An earlier study revealed that miR-let-7b is significantly associated with poor prognosis and short survival in patients with ovarian and hepatocellular cancers [14]. p53 is a pivotal tumour suppressor involved in DNA repair and cell cycle regulation. Literature shows that p53 inhibits HIV replication by inactivating the Tat protein among infected individuals [15]. Noteworthy, our previous study revealed lower levels of miR-155, miR-let-7b, and p53 in the serum of HIV + women compared with their HIV- counterparts [6]. The reason for the variation or switch of these miRNAs and p53 gene in serum and cervical cells is unknown. The low level of the biomarkers in the serum of HIV + women despite the high cellular levels could be associated with post-HIV-release degradation through uridylation or target-contact-related decay [16]. However, further studies are warranted to understand the miRNA and mRNA instability in the context of HIV.
Conversely, the lower expression of miR-182, miR-200c, and miR-125b in cervical cells of HIV + women raises questions about their roles in HIV-associated immune activation and epithelial transformation or their potential protective roles against cervical cancer among HIV- women. In a prior investigation, a similar expression pattern of miR-182, miR-200c and miR-125b was observed in the serum of HIV-positive women [6]. In contrast, previous research has reported upregulated miR-182 and downregulated miR-146a in HIV-uninfected patients with sepsis, demonstrating significant lymphopenia and depleted CD4 and CD8 T-cells [7]. This suggests that the downregulation of miR-182 is HIV-dependent. On the other hand, individuals diagnosed with melanomas exhibit reduced levels of miR-182 and miR-125b, which have been linked to shorter survival and an elevated risk of metastasis. This observation suggests that, during immune activation, HIV directly downregulate miR-182 and miR-125b through a yet-to-be-identified mechanism thereby malignant promoting epithelial transformation and disease progression. MiR-182 and miR-200c have been implicated in inhibiting cell migration and invasion, whereas miR-125b is known to target oncogenes and promote apoptosis by regulating host immunological response against bacterial and viral infections [17]. The higher levels of these miRNAs in HIV- women may suggest a tumour-suppressive effect that could mitigate cervical cancer risk in this group. However, further studies are required to elucidate the specific targets and pathways regulated by these miRNAs.
The small sample size used in this study may constitute a limitation. Further research on a large population is essential to validate these findings and unravel the underlying mechanisms behind miRNA variations. It may pave the way for conducting longitudinal studies to assess how changes in miRNA expression patterns over time correlate with cervical cancer development and disease progression and ultimately contribute to improved strategies for cervical cancer prevention, diagnosis, and treatment, especially in populations at elevated risk.