Recent advances in the contribution of noncoding RNAs to cisplatin resistance in cervical cancer

Mechanisms of action of CDDP

In 1978, CDDP became the first platinum compound to be approved for cancer treatment in the United States (Kelland, 2007), and since then, CDDP has proven to be one of the most effective drugs for the treatment of advanced or recurrent CC (Small et al., 2017). CDDP enters cells mainly by passive diffusion, with contributions from active transport via copper transporters (Holzer, Manorek & Howell, 2006; Ishida et al., 2002). While CDDP itself is inactive, it becomes chemically active in the cytoplasm when one or both of its chlorine atoms are displace by water molecules (Fig. 2) (Galluzzi et al., 2014; Kelland, 2000). Hydrolyzed CDDP exerts its toxic effects by forming DNA-platinum adducts and by simultaneously initiating cellular self-defense systems through the activation or silencing of multiple genes (Eastman, 1987; Yang et al., 2006). DNA damage triggers a complex array of DNA damage response and repair pathways; however, if these processes cannot repair CDDP-induced DNA damage, replication and transcription is blocked, and the cells undergo cell cycle arrest and/or apoptosis (Brabec & Kasparkova, 2005; Dasari & Tchounwou, 2014). The diverse mechanisms by which cells respond to platinum-induced DNA damage provides a wealth of potential mechanisms for cancer cells to evade drug-induced death. Indeed, any factor that influences CDDP binding to DNA, the DNA damage response, or pathways leading to apoptosis could potentially lead to the emergence of drug resistance (Shen et al., 2012). The responsible mechanisms were summarized in Fig. 3.

Mechanisms by which miRNAs affect CDDP resistance in CC

MiRNAs are short ncRNAs (generally <30 nucleotides) that play roles in post-transcriptional regulation (Lu & Rothenberg, 2018). In most instances, miRNAs act by binding to the 3′-untranslated region (3′-UTR) of the target mRNA, resulting in mRNA destabilization, degradation, or inhibition of translation. Various studies have reported abnormal miRNA expression in CC compared with normal cervical tissue (Juan et al., 2014; Lee et al., 2008), that could affect the proliferation and invasiveness of CC cells and thus their sensitivity to CDDP. Yang et al. (2016c) examined the relative expression of five miRNAs (miR-183, miR-182, miR-30a, miR-15b, and miR-16) and their potential target mRNAs in CDDP-resistant HeLa cell lines compared with their parent HeLa cell line, and they found that miR-182 and miR-15b were upregulated, while miR-30a was significantly downregulated, in the CDDP-resistant cells. Moreover, the mRNA targets of all these miRNAs were shown to be related to drug resistance.

Multiple miRNAs have been shown to influence CC cell growth, survival, and CDDP sensitivity via binding to the target mRNA 3′-UTR (Huang et al., 2017; Li et al., 2015; Sathyanarayanan, Chandrasekaran & Karunagaran, 2017; Yang et al., 2015a). For example, miR-217 binds to KRAS mRNA and directly targets it to mitigate the aggressiveness of CC cells (Yin & Ren, 2019). MiR-181a negatively regulates the expression of the apoptosis-related protein kinase Cδ (PRKCD) by targeting its mRNA for inhibiting apoptosis in CC cells (Chen et al., 2014). MiR-125a binds to STAT3 mRNA and inhibits its translation, resulting in downregulation of CC cell apoptosis and promotion of CDDP resistance (Fan et al., 2016). Finally, miR-144 targeting of the mRNA of LHX2, an oncogenic transcriptional regulator, was found to reverse the CDDP resistance of CC cells (Shi et al., 2019). In addition to these examples, miRNAs may affect CDDP sensitivity through the following mechanisms.

The mechanisms by which lncRNAs affect CDDP resistance in CC

LncRNAs (>200 nucleotides) play important roles in gene transcription, protein translation, and chromatin remodeling (Kornienko et al., 2013). Not surprisingly, lncRNAs have been shown to be involved in many of the pathological behaviors of CC cells, including aberrant proliferation, migration, and invasion (Dong et al., 2017; Liang et al., 2019; Liu et al., 2018b; Zhu et al., 2018). Recent evidence has confirmed the roles of lncRNAs in CDDP resistance in CC (Iden et al., 2016; Wang et al., 2018).

LncRNAs can act as competitive endogenous RNAs (ceRNAs) by inhibiting the ability of miRNAs to interact with the same target mRNAs (Wilusz, Sunwoo & Spector, 2009; Yamamura et al., 2018; Yoon, Abdelmohsen & Gorospe, 2014). Alterations in critical interactions of the ceRNA regulatory network may thus affect CDDP resistance in CC. HOXD antisense growth-associated lncRNA (HAGLR) has been shown to act as a ceRNA for miR-130a-3p, thereby upregulating the expression of the miR-130a-3p target mRNA zinc finger E-box binding homeobox 1 (Chi et al., 2018). Similarly, crosstalk between the lncRNA NCK1-DT, miR-134-5p, and MutS protein homolog 2 has been shown to play a role in CDDP resistance (Zhang et al., 2019). The lncRNAs cancer susceptibility candidate 2 (CASC2) and growth arrest-specific 5 (GAS5) both act as ceRNAs for miR-21. CASC2 binding to miR-21 upregulates PTEN expression, reducing the phosphorylation of AKT (Feng et al., 2017); whereas GAS5 binding to miR-21 decreases CC cell apoptosis via STAT3 mRNA (Yao et al., 2019). LncRNA DANCR functions as a ceRNA for miR-665, which regulates ERK–SMAD signaling in CC cells (Cao et al., 2019).

LncRNAs also affect CDDP resistance by direct regulation of signaling pathway components. Knockdown of the lncRNA plasmacytoma variant translocation 1 (PVT1) in the human CC cell line SiHa upregulates the level of active caspase-3, which increases CDDP-induced apoptosis (Iden et al., 2016). Similarly, lncRNA taurine-upregulated gene 1 (TUG 1) promotes CDDP resistance in the disease progression of CC through activating the MAPK pathway (Wei et al., 2019). Besides, upregulation of lncRNA MALAT1 increases the expression of phosphorylated PI3K and AKT in HeLa and C-33A cells and promotes their CDDP resistance (Wang et al., 2018).

Many other ceRNA–miRNA–mRNA regulatory networks that contribute to CDDP resistance undoubtedly exist, and expanding our understanding of those mechanisms will provide more therapeutic opportunities for overcoming CDDP resistance.

The mechanisms by which circRNAs affect CDDP resistance in CC

CircRNAs are endogenous ncRNAs which characterized by covalently closed loop without any 5′-3′ polarity or a polyadenylated tail (Chen & Yang, 2015). In recent years, increasing studies have found that circRNAs widespread expressed and played critical roles in biological processes such as tumor cell proliferation, apoptosis, invasion, and migration (Guo et al., 2014; Liu et al., 2018a; Memczak et al., 2013; Zhong et al., 2018). A study revealed 45 significantly highly expressed circRNAs in CC tissue through microarray analysis (Gao et al., 2017). Several studies have indicated that circRNAs were involved in CC development and progression by sponging miRNAs (Cai et al., 2019; Mao, Zhang & Li, 2019; Tang et al., 2019; Zhang et al., 2018b).

Since circRNAs can interact with miRNAs and modulate their expressions, they may also regulate the chemosensitivity of CDDP in CC. A study demonstrated that circMTO1 (mitochondrial translation optimization 1 homologue, ID: hsa_circ_0007874) could promote CC cell tumorigenesis and CDDP resistance through sponging miR-6893 (Chen et al., 2019). Another study identified hsa_circ_0023404 directly interacted with miR-5047 and inhibited autophagy-induced apoptosis to confer CDDP resistance of CC cells (Guo et al., 2019). CircRNAs play a significant role in chemoresistance of CC and may serve as future therapeutic biomarkers.

In addition to miRNAs, lncRNAs and circRNAs, piRNAs, as a new class of ncRNAs, have also shown a potential role in regulating CDDP resistance in CC. The upregulated expression of piR-651 was confirmed in HeLa cells, suggested that piRNAs may be involved in the development of CC (Cheng et al., 2011). Moreover, Hiwi, as a human homologue of the Piwi family and interacting with piRNAs, was found to be involved in the resistance of CC cells to CDDP (Liu et al., 2014). For most ncRNAs, our knowledge regarding their biological function is still limited, but their potential roles in pathogenesis and chemotherapy resistance of CC will be recognized in the future.