MicroRNAs in cervical cancer: evidences for a miRNA profile deregulated by HPV and its impact on radio-resistance

Abraham Pedroza-Torres, Eduardo López-Urrutia, Verónica García-Castillo, Nadia Jacobo-Herrera, Luis A Herrera, Oscar Peralta-Zaragoza, César López-Camarillo, David Cantú De Leon, Jorge Fernández-Retana, Jorge F Cerna-Cortés, Carlos Pérez-Plasencia, Abraham Pedroza-Torres, Eduardo López-Urrutia, Verónica García-Castillo, Nadia Jacobo-Herrera, Luis A Herrera, Oscar Peralta-Zaragoza, César López-Camarillo, David Cantú De Leon, Jorge Fernández-Retana, Jorge F Cerna-Cortés, Carlos Pérez-Plasencia

Abstract

Cervical carcinoma (CC) is one of the most common cancers and a leading cause of mortality in women worldwide. Epidemiologic and experimental data have clearly demonstrated a causal role of high-risk Human Papillomavirus (HR-HPV) types in CC initiation and progression, affecting the cellular processes by targeting and inactivating p53 and pRB host proteins. HR-HPV E5, E6 and E7 oncoproteins have the ability to deregulate several cellular processes, mostly apoptosis, cell cycle control, migration, immune evasion, and induction of genetic instability, which promote the accumulation of mutations and aneuploidy. In this scenario, genomic profiles have shown that aberrant expression of cellular oncogenic and tumor suppressive miRNAs have an important role in CC carcinogenesis. It has been stated that HPV infection and E6/E7 expression are essential but not sufficient to lead to CC development; hence other genetic and epigenetic factors have to be involved in this complex disease. Recent evidence suggests an important level of interaction among E6/E7 viral proteins and cellular miRNA, and other noncoding RNAs. The aim of the current review is to analyze recent data that mainly describe the interaction between HR-HPV established infections and specific cellular miRNAs; moreover, to understand how those interactions could affect radio-therapeutic response in tumor cells.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Expression of miRNAs through the cervical cancer progression. Human papillomavirus infects epithelial basal cells through mechanical microabrassions or by infecting directly the transformation zone, an abrupt transition from columnar to squamous epithelium. Infected parabasal cells actively express the early genes E1, E2, E4, and E5, E6 and E7 are expressed in limited quantities due to transcriptional modulation exerted by E2, which allows cells to have a higher cell-cycle progression. Infected basal cells migrate to the lumen as they differentiate expressing the late capsid genes L1 and L2. Several miRNAs have been associated with different clinical stages, including normal tissue, premalignant lesions (low and high grade squamous intraepithelial lesion, LSIL and HSIL, respectively) and invasive cancer represented at the bottom of the figure.
Figure 2
Figure 2
Canonical and non-canonical miRNA biogenesis pathways. RNA pol II transcribes a primary transcript called pri-miRNA which contains a 7-methylguanosine cap and poly(A) tail. Subsequently, this structure is degraded into the nucleus by an RNase type III known as Drosha; producing 70 nt long pre-miRNAs, which are exported to the cytoplasm by exportin-5. Once in the cytoplasm, pre-miRNAs are cleaved by RNase III endonuclease known as Dicer and associated proteins TRBP and PACT, resulting in a double stranded molecule called miRNA duplex. Then, the level of complementarity between miRNAs with their target mRNA could affect the following mechanism: if presented a total complementarity, mRNA degradation is carried out; on the contrary, if complementarity is partial, the inhibition of mRNA translation occurs.
Figure 3
Figure 3
Major molecular process regulated in radioresistant tumor cells.

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