The microRNA(miRNA)-34a is a key regulator of tumor suppression. It controls the expression of a plethora of target proteins involved in cell cycle, differentiation and apoptosis, and antagonizes processes that are necessary for basic cancer cell viability as well as cancer stemness, metastasis, and chemoresistance. In this review, we focus on the molecular mechanisms of miR-34a-mediated tumor suppression, giving emphasis on the main miR-34a targets, as well as on the principal regulators involved in the modulation of this miRNA. Moreover, we shed light on the miR-34a role in modulating responsiveness to chemotherapy and on the phytonutrients-mediated regulation of miR-34a expression and activity in cancer cells. Given the broad anti-oncogenic activity of miR-34a, we also discuss the substantial benefits of a new therapeutic concept based on nanotechnology delivery of miRNA mimics. In fact, the replacement of oncosuppressor miRNAs provides an effective strategy against tumor heterogeneity and the selective RNA-based delivery systems seems to be an excellent platform for a safe and effective targeting of the tumor.

The deeper understanding of non-coding RNAs has recently changed the dogma of molecular biology assuming protein-coding genes as unique functional biological effectors, while non-coding genes as junk material of doubtful significance. In the last decade, an exciting boom of experimental research has brought to light the pivotal biological functions of long non-coding RNAs (lncRNAs), representing more than the half of the whole non-coding transcriptome, along with their dysregulation in many diseases, including cancer.In this review, we summarize the emerging insights on lncRNA expression and functional role in cancer, focusing on the evolutionary conserved and abundantly expressed metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) that currently represents the best characterized lncRNA. Altogether, literature data indicate aberrant expression and dysregulated activity of MALAT1 in human malignancies and envision MALAT1 targeting as a novel treatment strategy against cancer.

Germline mutations of the tumour suppressor gene BRCA1 are involved in the predisposition and development of breast cancer and account for 20 -45% of all hereditary cases. There is an increasing evidence that these tumours are characterised by a specific phenotype and pattern of gene expression. We have hypothesised that differences in chemosensitivity might parallel molecular heterogeneity of hereditary and sporadic breast tumours. To this end, we have investigated the chemosensitivity of the BRCA1-defective HCC1937 breast cancer cell line, and the BRCA1-competent MCF-7 (hormone-sensitive) and MDA-MB231 (hormoneinsensitive) breast cancer cell lines using the MTT assay. The 50% inhibitory concentration (IC 50 ) for the individual compounds were derived by interpolate plot analysis of the logarithmic scalar concentration curve after a 48 h exposure. HCC1937 cells were significantly (Po0.005) more sensitive to cisplatin (CDDP) (IC 50 : 30-40 mM) compared with MCF-7 (IC 50 : 60-70 mM) and MDA-MB231 (IC 50 : 90 -100 mM) cells. On the other hand, BRCA1-defective breast cancer cells were significantly less sensitive to doxorubicin (Dox) (IC 50 : 45-50 mM) compared with MCF-7 (IC 50 : 1-5 mM) and MDA-MB231 (IC 50 : 5-10 mM) (Po0.02), as well as to paclitaxel (Tax) (IC 50 : 42 mM for HCC1937, 0.1 -0.2 mM for MCF-7 and 0.01 -0.02 mM for MDA-MB231) (Po0.001). Full-length BRCA1 cDNA transfection of BRCA1-defective HCC1937 cells led to the reconstituted expression of BRCA1 protein in HCC1937/ WT BRCA1-derived cell clone, but did not reduce tumour cell growth in soft agar. BRCA1 reconstitution reverted the hypersensitivity to CDDP (Po0.02), and restored the sensitivity to Dox (Po0.05) and Tax (Po0.001), compared with parental HCC1937 cells. Taken together, our findings suggest a specific chemosensitivity profile of BRCA1-defective cells in vitro, which is dependent on BRCA1 protein expression, and suggest prospective preclinical and clinical investigation for the development of tailored therapeutical approaches in this setting.

Purpose Deregulated expression of microRNAs (miRNAs) has been demonstrated in multiple myeloma (MM). A promising strategy to achieve a therapeutic effect by targeting the miRNA regulatory network is to enforce the expression of miRNAs that act as tumor suppressor genes, such as miR-34a. Experimental Design Here, we investigated the therapeutic potential of synthetic miR-34a against human MM cells in vitro and in vivo. Results Either transient expression of miR-34a synthetic mimics or lentivirus-based miR-34a-stable enforced expression triggered growth inhibition and apoptosis in MM cells in vitro. Synthetic miR-34a downregulated canonic targets BCL2, CDK6 and NOTCH1 at both the mRNA and protein level. Lentiviral vector-transduced MM xenografts with constitutive miR-34a expression showed high growth inhibition in SCID mice. The anti-MM activity of lipidic-formulated miR-34a was further demonstrated in vivo in two different experimental settings: i) SCID mice bearing non-transduced MM xenografts; and ii) SCID-synth-hu mice implanted with synthetic 3D scaffolds reconstituted with human bone marrow stromal cells and then engrafted with human MM cells. Relevant tumor growth inhibition and survival improvement were observed in mice bearing TP53-mutated MM xenografts treated with miR-34a mimics in the absence of systemic toxicity. Conclusions Our findings provide a proof-of-principle that formulated synthetic miR-34a has therapeutic activity in preclinical models and support a framework for development of miR-34a-based treatment strategies in MM patients.

Purpose Deregulated expression of microRNAs (miRNAs) plays a role in the pathogenesis and progression of multiple myeloma (MM). Among upregulated miRNAs, miR-21 has oncogenic potential and therefore represents an attractive target for the treatment of MM. Experimental design Here, we investigated the in vitro and in vivo anti-MM activity of miR-21 inhibitors. Results Either transient enforced expression or lentivirus-based constitutive expression of miR-21 inhibitors triggered significant growth inhibition of primary patient MM cells or IL-6-dependent/independent MM cell lines and overcame the protective activity of human bone marrow stromal cells. Conversely, transfection of miR-21 mimics significantly increased proliferation of MM cells, demonstrating its tumor promoting potential in MM. Importantly, upregulation of miR-21 canonical validated targets (PTEN, Rho-B and BTG2), together with functional impairment of both AKT and ERK signaling, were achieved by transfection of miR-21 inhibitors into MM cells. In vivo delivery of miR-21 inhibitors in SCID mice bearing human MM xenografts expressing miR-21 induced significant anti-tumor activity. Upregulation of PTEN and downregulation of p-AKT were observed in retrieved xenografts following treatment with miR-21 inhibitors. Conclusions Our findings show the first evidence that in vivo antagonism of miR-21 exerts anti-MM activity, providing the rationale for clinical development of miR-21 inhibitors in this still incurable disease.