Abstract
Cervical cancer is the fourth leading cause of cancer-related death among women worldwide. The chemotherapeutical agent cisplatin, a small platinum-based compound, is considered as the standard therapy for locally advanced cervical cancer or recurrent cancers, sometimes in combination with radiotherapy or other drugs. However, drug resistance and radio-resistance phenomena could reduce the life expectancy of cervical cancer patients. Resistance mechanisms are complex and often involve multiple cellular pathways in which microRNAs (miRNAs) play a fundamental role. miRNAs are a class of endogenous non-coding small RNAs responsible for post-transcriptional gene regulation. Convincing evidence demonstrates that several deregulated miRNAs are important regulators in the onset of drug and radioresistance in cervical cancer, thus underlying their potential applications in a clinical setting. In this review, we summarized the mechanisms by which miRNAs affect both cisplatin and radioresistance in cervical cancer. We also described the regulatory loops between miRNAs and lncRNAs promoting drug resistance. Besides, we reported evidence for the role of miRNAs in sensitizing cancer cells to cisplatin-based chemotherapy, and provided some suggestions for the development of new combined therapies for cervical cancer.
Highlights
Cervical cancer represents the fourth most common cancer in females worldwide [1] with 570,000 women diagnosed each year
Despite the fact that studies have demonstrated the value of the use of neoadjuvant cisplatin-based chemotherapy (NACT) to treat Federation of Gynecology and Obstetrics (FIGO) stage IB2, IIA2, and IIB, compared to the primary surgery treatment (PST) [14], cisplatin has been considered the primary chemotherapy for locally advanced cervical cancer (LACC) or recurrent cancers, even in combination with radiotherapy or other drugs [15,16]
Since Phosphatase and Tensin Homolog (PTEN) plays an important role in suppressing the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which is associated with chemotherapeutic drug resistance in cancer cells [79,80,81], its inhibition leads to a PI3K/AKT activation with a consequent increase in cell survival and apoptosis inhibition through phosphorylating of the downstream targets [82,83,84] (Figure 4A,B)
Summary
Cervical cancer represents the fourth most common cancer in females worldwide [1] with 570,000 women diagnosed each year (www.who.int, accessed on 10 January 2021). The National Cancer Institute Alert demonstrated the superiority of cisplatin-containing concurrent chemoradiotherapy for the treatment of advanced cervical cancer [11]. Based on this evidence, over time the chemotherapeutical agent cisplatin, a small platinumbased compound, became the worldwide standard for chemotherapy [12,13]. Despite the fact that studies have demonstrated the value of the use of neoadjuvant cisplatin-based chemotherapy (NACT) to treat FIGO stage IB2, IIA2, and IIB, compared to the primary surgery treatment (PST) [14], cisplatin has been considered the primary chemotherapy for locally advanced cervical cancer (LACC) or recurrent cancers, even in combination with radiotherapy or other drugs [15,16]. Despite the evidence for clinical and phenotypical variables able to classify patients according to the response to treatment, the comprehension of the molecular mechanisms in determining drug and radioresistance could promote the advance to a personalized medicine approach, in which molecular biomarker can find a relevant decisional role
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