Journal of Aging Research of indolent CLL. In contrast, miR-29 is downregulated in aggressive CLL when compared to indolent CLL, and miR-29 may function as a tumor suppressor in CLL by targeting T- cell leukemia/lymphoma 1 (TCL-1) [50]. In addition, miR- 30 directly represses LIN28 (a lin-28 homolog of C. elegans) in embryonic stem cells and cancer cells. Importantly, LIN28 functions as an oncogene promoting malignant transforma- tion and tumor progression [51]. Another miRNA involved in senescence is miR-449a. miR-449a induces senescence by suppressing Rb phosphorylation by directly repressing the upstream regulatory factors of Rb, such as cyclin D1 (CCND1) [53], histone deacetylase 1 (HDAC1) [53], cyclin- dependent kinase 6 (CDK6), and cell division cycle 25 homolog A (CDC25A) [54]. A recent study has shown that miR-449a is downregulated in prostate cancer, indicating that this miRNA regulates cell growth and viability, in part by repressing the expression of HDAC-1 [53]. The functional role of miR-128a in senescence is also evident. miR-128a directly targets the Bmi-1 oncogene (polycomb ring ﬁnger oncogene; BMI1), increasing p16INK4A expression and reactive oxygen species (ROS), which pro- mote cellular senescence in medulloblastoma cell lines [55]. Recently, it has been reported that this tumor suppressive miRNA (miR-128a) is downregulated in medulloblastomas [55], glioblastomas [56], and acute myeloid leukemia [57], suggesting that this miRNA has an important role in these types of cancer. miR-217, which is expressed in endothelial cells dur- ing aging, promotes premature senescence by inhibiting SIRT1 expression, thus increasing forkhead box O1 (FoxO1) expression and endothelial nitric oxide synthase (eNOS) acetylation [58]. In addition, miR-217 has been reported to be a novel tumor suppressive miRNA in pancreatic ductal adenocarcinoma due to decreases in tumor cell growth both in vitro and in vivo by targeting K-Ras [59]. miR-290 also acts as a physiological eﬀector of senescence in murine cells including mouse embryonic ﬁbroblasts (MEFs) [76], and miR-20a induces senescence in MEFs through the direct downregulation of the transcriptional regulator leukemia/lymphoma-related factor (LRF), leading to an induction of p19ARF [75]. In addition, miR-519 is another miRNA that induces senescence in cancer cell lines. miR-519 elicits these actions by repressing HuR expression [52]. On the other hand, there are miRNAs that are downregulated during senescence, such as miR-15b, miR- 24, miR-25, and miR-141, which directly target mitogen- activated protein kinase kinase (MKK4) [71]. Importantly, the escape from OIS is a requirement for transformation into tumor cells. Therefore, high-throughput genomic and miRNA screens have been preformed to iden- tify novel mediators of OIS in human mammary epithelial cells (HMECs), which contain OHT-inducible RasG12V [60]. Borgdorﬀ and colleagues showed that 28 miRNAs prevented senescence upon RasG12V induction. These miRNAs are as follows: miR-17-5p, miR-20a-b, miR-93, miR-106a-b, miR- 130b, miR-302a-d, miR-372, miR-373, miR-512-3p, miR- 515-3p, miR-519c-e, miR-520a-g, miR-526b∗, and miR- 146a-b. These miRNAs bypass RasG12V-induced senescence by directly targeting the 3 -UTR of p21Cip1. Moreover, 5 miR-372, miR-373, miR-302, and miR-520 can also bypass RasG12V-induced senescence through the downregulation of LATS2 in addition to p21Cip1 [60–63]. miR-372 and miR-373 also prevent Ras-induced senescence in human ﬁbroblasts [61], suggesting that the immortalization mechanism of these miRNAs is universal. Importantly, these identiﬁed pro- liferative miRNAs have been demonstrated to be associated with cancer development. For example, miR-17-5p is overex- pressed in pancreatic cancer [64], squamous cell carcinoma [65], breast cancer [66], hepatocellular cancer [67], renal cell carcinoma [68], and thyroid cancer [69], suggesting a potential oncogenic role of miR-17-5p. Furthermore, miR- 130b promotes gastric cancer by downregulating the tumor suppressor, runt-related transcription factor 3 (RUNX3) [70]. In addition, miR-372 and miR-373 have been found to be upregulated in testicular germ cell tumors [61]. Finally, miR-302 is expressed speciﬁcally in embryonic stem cells and embryonic carcinoma cells [77, 78], suggesting a possible role of this miRNA in cancer stem cell biology. 4. Senescence Induction Based upon miRNA Modulation as a Therapeutic Approach It is well known that the overexpression of several oncogenes (e.g., RasG12V) or tumor suppressor genes (e.g., ribosomal protein S6 kinase, 90 kDa, polypeptide 6; RSK4) [79] induces senescence. However, cancer cells can be induced to a senescent state with conventional anticancer treatments such as Doxorubicin [80, 81]. The use of senescence as a novel modality of cancer therapy has been considered in clinical trials with promising results [81]. Senescence may promote carcinogenesis in surrounding tissues [82] by secreting interleukins, chemokines, growth factors, and proteases, which stimulate malignant pheno- types in neighboring cells. In this regard, miR-146a and miR-146b have been demonstrated to negatively regulate the senescence-associated secretion of IL-6 and IL-8 by directly targeting IRAK1 and reducing NF-κB activity [83]. There- fore, these miRNAs may be promising tools to restore the protective potential against development of the senescence- associated secretory phenotype (SASP). The rationale for using miRNAs as novel anticancer molecules is based on the following two major ﬁndings: (1) miRNA expression is deregulated in cancer when compared with normal tissues; (2) the cancer phenotype can be changed by targeting miRNA expression [13]. The therapeutic application of miRNAs involves two major strategies. For oncogenic miRNAs (oncomirs), which promote proliferation when overexpressed, the major thera- peutic strategy is directed toward reducing oncomir expres- sion. These therapies include anti-miRNA oligonucleotides, microRNA sponges, miRNA masking, and small molecule inhibitors. For TS-miRs, the therapeutic strategy is directed toward restoring the levels of TS-miRs by exogenous expres- sion (Figure 3). 4.1. Anti-miRNA Oligonucleotides. The base pair interaction between miRNAs and mRNAs is essential for the function of