One of the major challenges in oncology is drug resistance, which triggers relapse and shortens patients’ survival. In order to promote drug desensitization, cancer cells require the establishment of an ideal tumor microenvironment that accomplishes specific conditions. To achieve this objective, cellular communication is a key factor. Classically, cells were believed to restrictively communicate by ligand-receptor binding, physical cell-to-cell interactions and synapses. Nevertheless, the crosstalk between tumor cells and stroma cells has also been recently reported to be mediated through exosomes, the smallest extracellular vesicles, which transport a plethora of functionally active molecules, such as: proteins, lipids, messenger RNA, DNA, microRNA or long non-coding RNA (lncRNAs). LncRNAs are RNA molecules greater than 200 base pairs that are deregulated in cancer and other diseases. Exosomal lncRNAs are highly stable and can be found in several body fluids, being considered potential biomarkers for tumor liquid biopsy. Exosomal lncRNAs promote angiogenesis, cell proliferation and drug resistance. The role of exosomal lncRNAs in drug resistance affects the main treatment strategies in oncology: chemotherapy, targeted therapy, hormone therapy and immunotherapy. Overall, knowing the molecular mechanisms by which exosomal lncRNA induce pharmacologic resistance could improve further drug development and identify drug resistance biomarkers.

Neuroblastoma (NB) deriving from neural crest cells is the most common extra-cranial solid cancer at infancy. NB originates within the peripheral sympathetic ganglia in adrenal medulla and along the midline of the body. Clinically, NB exhibits significant heterogeneity stretching from spontaneous regression to rapid progression to therapy resistance. MicroRNAs (miRNAs, miRs) are small (19-22 nt in length) non-coding RNAs that regulate human gene expression at the post-transcriptional level and are known to regulate cellular signaling, growth, differentiation, death, stemness, and maintenance. Consequently, the function of miRs in tumorigenesis, progression and resistance is of utmost importance for the understanding of dysfunctional cellular pathways that lead to disease evolution, therapy resistance, and poor clinical outcomes. Over the last two decades, much attention has been devoted to understanding the functional roles of miRs in NB biology. This review focuses on highlighting the important implications of miRs within the context of NB disease progression, particularly miRs’ influences on NB disease evolution and therapy resistance. In this review, we discuss the functions of both the “oncomiRs” and “tumor suppressor miRs” in NB progression/therapy resistance. These are the critical components to be considered during the development of novel miR-based therapeutic strategies to counter therapy resistance.

Aim: Aberrant microRNA expression is a common event in cancer drug resistance, however its involvement in malignant pleural mesothelioma (MPM) drug resistance is largely unexplored. We aimed to investigate the contribution of microRNAs to the resistance to drugs commonly used in the treatment of MPM.

Methods: Drug resistant MPM cell lines were generated by treatment with cisplatin, gemcitabine or vinorelbine. Expression of microRNAs was quantified using RT-qPCR. Apoptosis and drug sensitivity assays were carried out following transfection with microRNA mimics or BCL2 siRNAs combined with drugs.

Results: Expression of miR-15a, miR-16 and miR-34a was downregulated in MPM cells with acquired drug resistance. Transfection with miR-15a or miR-16 mimics reversed the resistance to cisplatin, gemcitabine or vinorelbine, whereas miR-34a reversed cisplatin and vinorelbine resistance only. Similarly, in parental cell lines, miR-15a or miR-16 mimics sensitised cells to all drugs, whereas miR-34a increased response to cisplatin and vinorelbine. Increased microRNA expression increased drug-induced apoptosis and caused BCL2 mRNA and protein reduction. RNAi-mediated knockdown of BCL2 partly recapitulated the increase in drug sensitivity in cisplatin and vinorelbine treated cells.

Conclusion: Drug-resistant MPM cell lines exhibited reduced expression of tumour suppressor microRNAs. Increasing tumour suppressor of microRNA expression sensitised both drug resistant and parental cell lines to chemotherapeutic agents, in part through targeting of BCL2. Taken together, these data suggest that miR-15a, miR-16 and miR-34a are involved in the acquired and intrinsic drug resistance phenotype of MPM cells.

Aim: ABCB1 is a major player in cancer drug resistance. The purpose of this study was to functionally assess the regulation of ABCB1 activity in a doxorubicin-resistant breast cancer cell line by miR-200c and miR-203.

Methods: Human breast carcinoma cell lines MCF-7 (Doxorubicin-sensitive and not expressing ABCB1) and KCR (Doxorubicin-resistant and expressing ABCB1) were used to evaluate the expression levels of miR-200c and miR-203 by Real-time quantitative PCR (RT-qPCR). The effects of transient ectopic expression of miRNA-200c and miR-203 on the expression of ABCB1 in KCR and MCF-7 cells was verified by RT-qPCR and Western Blot. The extrusion activity of the ABCB1 pump was analyzed by fluorescence microscopy and flow cytometry through fluorescence substrate retention assays (DiOC₂) in the presence and absence of the ABCB1 inhibitor verapamil.

Results: RT-qPCR results indicated a 100,000-fold increase in ABCB1 mRNA expression levels in KCR cells compared to MCF-7 cells, and is inversely correlated with the expression of miR-203 and miR-200c. The insertion of miR-200c and miR-203 led to a higher retention of DiOC₂ within KCR cells, and slightly reduced the protein levels of ABCB1 in KCR cells, although the high initial expression of ABCB1 masked the reduction in protein levels. The increased intracellular accumulation of the fluorescent due DiOC₂ in the presence of the ABCB1 inhibitor verapamil correlated with the inhibition caused by miR-203 and miR-200c in transfected cells.

Conclusion: The present study demonstrates that miR-200c and miR-203 exert a negative modulating effect on the activity of ABCB1 associated with doxorubicin resistance.

Despite several advances in targeted therapies for breast cancer, breast-cancer-associated death remains high in women. This is partially due to the lack of reliable markers predicting metastatic disease or recurrence after initial therapy. Recent research into the clinical validity of circulating cancer-specific biomarkers as a “liquid biopsy” is of growing interest. Of these, exosomal microRNAs (miRNAs) are promising candidate biomarkers for clinical use in breast cancer. In addition to their diagnostic value, exosomal miRNAs play an important role in predicting clinical outcome or treatment response. In this review, it is focused on the findings concerning exosomal miRNAs in relation to disease detection, prognostic impact and therapeutic effect in breast cancer, and discuss their clinical utility.

Aim: Neoadjuvant chemotherapy may represent a shift in the treatment of locally advanced colon cancer. The angiogenic couple has-microRNA-126 (miRNA-126) and epidermal growth factor-like domain 7 (EGFL7) are transcribed from the same gene and regulates all aspects of angiogenesis and may influence the ability of tumor cells to disseminate. The aim was to analyze the relationship between miRNA-126 and EGFL7 and disease recurrence in patients with locally advanced colon cancer treated with neoadjuvant chemotherapy.

Methods: This study included 71 patients from a phase II study all planned for three cycles of capecitabine and oxaliplatin before surgery. Blood was sampled at baseline and right before and after the operation. Circulating miRNA-126 was analysed by RT-qPCR and a quantitative immunoassay was used for the analyses of EGFL7.

Results: The rates of 5-year disease-free survival (DFS) and overall survival (OS) were 80% and 85%, respectively. The level of circulating miRNA-126 before the operation predicts recurrence, P = 0.035. In patients with values below and above the median the recurrence rate was 31% and 4%, respectively. Similar results applied to EGFL7. A combined estimate identified a subgroup of patients (25 of 71) with no recurrence and a 5-year DFS and OS rate of 100%, respectively.

Conclusion: MicroRNA-126 and EGFL7 are predictors for disease recurrence in patients with locally advanced colon cancer treated with neoadjuvant chemotherapy and may assist in selection of adjuvant chemotherapy.

Ovarian cancer has a poor outcome because it is usually detected at advanced tumor stages, and the majority of the patients develop disease relapse as a result of chemotherapy resistance. This most lethal gynecological malignancy metastasizes within the peritoneal fluid or ascites to pelvic and distal organs. In ovarian cancer progression and metastasis, small non-coding RNAs (ncRNAs), including long noncoding RNAs and microRNAs have been recognized as important regulators. Their dysregulation modulates gene expression and cellular signal pathways and can be detected in liquid biopsies. In this review, we provide an overview on circulating plasma and serum ncRNAs participating in tumor cell migration and invasion, and contributing to recurrence and metastasis of ovarian cancer. We will also discuss the development of potential, novel therapies using ncRNAs as target molecules or tumor markers for ovarian cancer.

Non-protein coding RNAs have emerged as a regulator of cell signaling and cancer progression through regulation of cell proliferation, metastatic burden, and cancer stem cell capacity. A subtype of non-protein coding RNA is long non-protein coding RNA (lncRNA). Besides their aforementioned roles in cancer cell biology, dysregulation of lncRNAs contribute to resistance to therapeutic treatments. A couple of important therapeutic classes are chemotherapy and targeted/hormone therapies. This review highlights the variety of malignancies affected by lncRNA dysregulation and the underlying mechanism causing therapeutic resistance.

MicroRNAs (miRNAs), a group of small regulatory noncoding RNAs, transformed our thinking on gene regulation. More than two thousand human miRNAs have been identified thus far. These bind imperfectly to the 3’-untranslated region of target mRNA and have been involved in several pathological conditions including cancer. In fact, major hallmarks of cancer, such as the cell cycle, cell proliferation, survival and invasion are modulated by miRNAs. Cancer drug resistance (CDR) has also been described as being modulated by miRNAs. CDR remains a burden for cancer therapy and patients’ outcome, often resulting in more aggressive tumours that tend to metastasize to distant organs. In this review we discuss the role of miRNAs influencing drug metabolism and drug influx/efflux, two important mechanisms of CDR.