Influence of DDP Chemotherapy on miRNA Expression: History
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Contributor:
Maria Konoshenko
,
Yuriy Lansukhay
,
Sergey Krasilnikov
,
Pavel Laktionov

Platinum-based chemotherapy, cisplatin (DDP) specifically, is the main strategy for treating lung cancer (LC). However, there is a lack of predictive drug-resistance markers, and there is increased interest in the development of a reliable and sensitive panel of markers for DDP chemotherapy-effectiveness prediction. MicroRNAs represent a perspective pool of markers for chemotherapy effectiveness.

  • lung cancer
  • non-small cell lung cancer
  • cisplatin
  • DDP
  • chemotherapy
  • chemosensitivity

1. Cisplatin and Lung Cancer Chemotherapy

The main method of lung cancer (LC) treatment is chemotherapy. Platinum-based drugs are the gold-standard first-line treatments (ASCO and NCCN). The use of platinum-based drugs (cisplatin and carboplatin), including in combination with other chemotherapy agents (taxanes, pemetrexed, and antimetabolites), can achieve an overall survival for patients of 8 to 10 months on average [1]. A large and randomized comparison of four co-therapy regimens for stage IIIb and IV LC (cisplatin and paclitaxel, cisplatin and gemcitabine, cisplatin and docetaxel, and carboplatin and paclitaxel), which are the most commonly used regimens in clinical practice, showed that none of the used regimens had advantages over the others. The overall survival for all the studied regimens was about 10 months, with a one-year survival rate of 34% [2]. Patients with stage III LC undergo chemoradiotherapy (sequentially or simultaneously). This chemotherapy regimen is based on the basic drugs of the platinum group or their combination with other chemotherapy drugs, i.e., paclitaxel, etoposide, and vinblastine. The median progression-free survival of patients treated with chemoradiotherapy is poor (approximately eight months), with a five-year survival rate of only 15% [3]. An option to improve the situation is to switch to other treatment regimens, or example, treatment using the immunotherapy drug durvalumab, which is an inhibitor of the PDL 1 ligand that mobilizes the effector link of the antitumor immune system in a tumor microenvironment [4] or treatment of EGFR-positive LC patients using a combination of chemotherapy and tyrosine kinase inhibitors (platina-based chemotherapy and osemertinib) [5]. These chemotherapy schemes can achieve longer remission. However, these treatments have some limitations: immunotherapy is not available in all countries [6] and only about 15% of the general population of NSCLC patients have mutations in the EGFR gene [6][7].
Thus, platinum-based chemotherapy continues to be the main strategy for treating lung cancer [1][8]. Cisplatin (DDP) is the most widely used chemotherapy agent; it is an alkylating agent that effects inter- and intra-strand DNA cross-links, leading to cell-cycle arrest. However, drug resistance can develop, resulting in further development of a tumor and side effects such as myelosuppression, drug nephritis, nausea, vomiting, hearing loss, and polyneuropathy, which significantly reduce a patient’s quality of life [9]. Acquired chemoresistance during treatment is a major problem for clinicians and is a major cause of therapeutic failure [10]. Various mechanisms of tumor resistance to DDP have been described, and, most recently, these mechanisms have been classified as follows: (1) pre-target resistance (before cisplatin binds to DNA), (2) target resistance (directly associated with DNA-cisplatin adducts), (3) post-target resistance (associated with apoptosis caused by DDP-mediated DNA damage), and (4) off-target resistance (affecting molecular mechanisms that do not present obvious links to DDP-induced signals) [10]. Regardless of the resistance type, a tumor’s loss of sensitivity to DDP leaves a very short period of time for therapy correction aimed at increased patient survival. Clinical outcomes in the treatment of LC patients could be significantly improved through the introduction of non-invasive biomarker assays to predict and monitor the effectiveness of therapy [11]. However, there is a lack of reliable predictive drug-resistance markers and an urgent need to develop reproducible and highly sensitive panels of predictive markers for DDP-effectiveness assessment. Knowing a tumor’s response to cisplatin in advance would help clinicians, both before and during treatments, to select effective drugs and to adjust chemotherapy programs from one option to another in a timely manner. Efforts to identify such markers have primarily focused on the mechanisms underlying DDP resistance. DDP-resistance regulation represents a complicated network of many factors and signaling pathways. Obviously, a set of markers is needed to detect different types of tumors and, subsequently, to highlight the typical principal or driving aberrations specific to a particular tumor. MicroRNAs (miRNAs) could be promising candidate biomarkers for DDP resistance in LC, due to the multiple mechanisms by which they regulate the expression, and vice versa, for different target genes. Fortunately, there is considerable evidence on the association of aberrant miRNAs expression with DDP resistance in tumor cells.

2. MicroRNAs and Lung Cancer Chemotherapy

Since miRNAs regulate of a wide spectrum of physiological and pathological processes in cells, they are secreted from cells and enter the extracellular medium and biological fluids [12]. MicroRNAs have been shown to be rather stable in biological fluids, including blood or bronchial lavage, in which they circulate in tight complexes with biopolymers or are packed in membrane-coated vesicles [13][14] for review. Cell-free miRNAs (cfmiRNAs) can be released from different tumor areas or tumor nodes, and, therefore, a cfmiRNA profile reflects a patient’s generalized tumor phenotype. Considering the well-developed protocols for cfmiRNA isolation and evaluation of their sets and concentrations, cfmiRNAs could be promising diagnostic markers [15]. The availability of liquid media, such as blood, sputum, and saliva, and methods that do not require invasive procedures have provided an opportunity for using liquid biopsies in the diagnosis of cancers, including LC [16]. The correlation between changes in miRNA expression and tumor development during treatment (aggressiveness and chemoresistance) have prompted the development of miRNA diagnostic panels and the emergence of prognostic and predictive markers for monitoring cancer as well as the development of new strategic solutions for the treatment of platinum-resistant LC ([17][18][19] for review). In fact, miRNA dysregulation in LC and under LC chemotherapy is involved in the regulation of the genes crucial to chemoresistance development: DNA repair, apoptosis, cell-cycle regulation, epithelial–mesenchymal transition (EMT), hypoxia, autophagy, drug efflux, cancer stem-cells activation (CSCs), etc. [19][20][21].
Numerous studies have aimed at identifying the miRNAs that mediate DDP response by investigating miRNAs that induce resistance/sensitivity to DDP in tumor cells or through comparative analyses of miRNA expressions in chemo-resistant and chemo-sensitive samples (cell lines and the tissues or biofluids of DDP-resistant and -sensitive LC patients). However, there are fewer studies that have aimed at exploring miRNAs differentially expressed under DDP chemotherapy.

3. Influence of DDP Chemotherapy on miRNA Expression

DDP chemotherapy, both as a powerful anticancer treatment and as a strong stressful intervention in organisms, causes significant changes in miRNA expression in tumor cells, as well as in many different normal cell types. However, until now, limited attention has been given to the analysis of the effect of DDP chemotherapy on the expression of miRNAs (Table 1).
Table 1. The effect of DDP on miRNA level in LC samples.
No. DDP R/DDP S
miRNA		 Downstream Regulated Target In DDP R vs. DDP S Samples Effect of DDP on miRNA Level ↑ of miRNA Expression → Chemoresistance ↓ of miRNA Expression → Chemosensitivity Model: R/S Cells; Mice Xenografts Reference
Gene, Main Function/Pathway Methods
1 miR-33b-3p P21 luciferase assay, RT-PCR, Western blot   ↓ in cells ↑ cell viability, proliferation, promoted G1/S transition, DNA-damage response ↓ cell viability, G1 arrest, S: A549
R: A549/DDP		 [22]
2 miR-425-3p AKT1, autophagy luciferase
assay, qRT-PCR, Western blot		 ↑ in cells, cells exosomes ↑ in serum exosomes, cell exosomes ↑ cell viability, ↓ apoptosis in S cells ↓ cell viability, ↑ apoptosis in R cells S: A549
R: A549/DDP		 [23]
3 miR-3195       ↑ in cells, cell exosomes     S: A549 [24]
4 miR-3676-5p       ↑ in cells, cell exosomes     S: A549
5 miR-4443       ↑ in cells, cell exosomes     S: A549
6 Let7 (let-7a,-7b,-7c,-7d,-7e, -7f,-7g,-7i) LIN28A,B luciferase assay, IHC, RT-PCR, Western blot ↓ in tissues, cells ↓ in cells ↓ cell viability in R cells ↑ cell viability in S cells S: A549 R: A549/DDP [25]
7 miR-29c AKT2 RT-PCR ↓ in tissues ↑ in cells ↓ cell viability in S
↓ tumor volume, proliferation (ki-67,AKT2) in X		 ↑ cell viability S: SPC-A-1, A549
X: A549		 [26]
8 miR-32 TRIM29   ↓ in plasma ↑ in plasma       [27]
9 miR-181a       ↑ in cells ↑ percentage of A549 cells with a G0-G1 DNA content
↑ proteolytic maturation of caspase-9 and caspase-3 triggered by CDDP
↑ proapoptotic member of the Bcl-2 family Bax		 No effect S: A549 [10]
10 miR-1244 Bax, MEF2D, cyclin D1, p53 qRT-PCR, Western blot   ↓ in cells ↓ proliferation, ↑ apoptosis   S: A549, H522 [28]
DDP—cisplatin; DDP-S miRNA—miRNA associated with DDP sensitivity; DDP-R miRNA—miRNA associated with DDP resistance; R—chemotherapy-resistant cell line; S—chemotherapy-sensitive cell line; X—mice xenograft based on LC cell lines.
Nevertheless, miRNAs deregulated by DDP therapy represent a pool of prospective biomarkers for the development of a co-therapy, because they may reflect the development of a secondary resistance to DDP, which, in turn, may be influenced by changes in miRNA-expression levels. Liquid-biopsy studies [23] are of special interest, because they allow continuous observation of changes in miRNA-expression levels during LC therapy. However, such studies are only at their starting point and require normal-tissue DDP-response filtering.
There are also some studies that have aimed to associate miRNA expression with simultaneous resistance/sensitivity to different chemotherapies, including DDP (Table 2). They include investigations of DDP and other platinum-based drugs, taxanes, cytostatic vincristine, and cetuximab (IgG1 against epidermal growth factor, Table 2). The results of such studies have indicated that miRNAs are involved in the regulation of drug resistance via both common and different drug mechanisms, including multidrug resistance.
Table 2. miRNA and resistance to DDP and other chemotherapies.
No. DDP R/DDP S miRNA ↑ of miRNA Expression ↓ of miRNA Expression Model: (1) R/S Cells (2) Mice Xenografts Drug Reference
1 miR-181a ↑ migration, invasion, EMT in S ↓ migration, invasion, EMT in R cells S: A549
R: A549/PTX, A549/DDP		 DDP, paclitaxel [29]
2 Let7f
miR-29a		 ↓ cell viability in S, R   S: H2030 cells DDP, carboplatin [30]
3 miR-34c-3p ↓ cell viability, migration; ↑ apoptosis in cells
↓ tumor weight in X		   S: A549, H1299
X: A549 mice		 DDP, taxol [31]
4 miR-137 ↓ cell proliferation, migration, induced cell apoptosis, arrested cell cycle in G1 phase and reversed drug resistance in R cells;
↓ tumor volume, weight, VEGF (angiogenesis) in X		 ↑ cell growth, migration, cell survival, cell-cycle G1/S transition, resistance (CCK-8 assay) in S cells S: A549
R: A549/CDDP
X: A549/CDDP		 DDP, paclitaxel [32]
5 miR-200c ↓ cell viability, proliferation invasion, EMT; ↑ apoptosis   S: H1299, H596, and H522 DDP, cetuximab [33]
6 miR-202 ↓ cell viability, IC50; ↑ apoptosis in S;
↓ tumor volume in X		   S: NCI-H441, A549
X: A549		 DDP [26]
↓ IC50 in S Oxaliplatin, carboplatin
7 miR-216b ↓ IC50; ↓ tumor weight in X ↑ IC50 S: A549, PC9 DDP, carboplatin, oxaliplatin [34]
8 miR-495 ↓ cell viability, intracellular DDP accumulation in S, R ↑ cell viability S: A549
R: A549/DDP		 DDP, carboplatin, trans-/-diaminocyclohexaneoxalatoplatinum [35]
9 miR-497 ↓ cell viability, ↑ apoptosis in R ↑ cell viability in S S: A549
R: A549/DDP		 DDP, vincristine [36]
DDP—cisplatin; DDP-S miRNA—miRNA associated with DDP sensitivity; DDP-R miRNA—miRNA associated with DDP resistance; R—chemotherapy-resistant cell line; S—chemotherapy-sensitive cell line; X—mice xenograft based on LC cell lines.

This entry is adapted from the peer-reviewed paper 10.3390/ijms23147594

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