Insensitivity To Anti Growth Signals Biology Essay

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The miR-17~92 cluster is also essential for integrating signals during the G1 phase of the cell cycle and deciding whether a signal should be interpreted as proliferative or apoptotic [29]. In physiological conditions, the miR-17~92 cluster can limit MYC activation by dampening the E2F positive feedback loop. In tumors with MYC activation, miR-17~92 cluster protects cells from MYC-induced apoptotic E2F responses, leading to uncontrolled cellular proliferation.

The oncomiR-17~92 is found upregulated in many lymphoproliferative disorders [30] and solid cancer, not only through MYC activation, but also through genomic amplification or BCR-ABL regulation [31] or retroviral insertion [32].

Bypass of antigrowth signals such as cyclin dependent kinase (CDK) inhibition in tumors is achieved at the post-transcriptional level by overexpression of miRNAs from two distinct clusters (miR-106b~93 and miR-222-221). These miRNAs are overexpressed in gastric cancer[33] and have been found to directly repress the entire Cip/Kip family members of Cdk inhibitors (p57Kip2, p21Cip1 and p27Kip1) [33]. Just recently another miRNA found upregulated in gastric cacner, miR-27a has been shown to act as an oncogene [34]. miR-27a promotes cancer growth via inhibition of prohibitin, an anti-proliferative protein, regulator of cell-cycle progression and apoptosis [34].

3) EVASION FROM APOPTOSIS. Apoptosis is a physiological self-destruction cellular mechanism leading to removal of unwanted cells. The cancer associated genomic region 1p36, frequently lost or rearranged in many tumor types, including those originating from neural, epithelial and hematopoietic tissues, contains as candidate tumor suppressors the miR-34a. The tumor suppressive function of this gene has been extensively studied in human neuroblastomas [35] [36], where its loss synergizes with MYCN amplification. This is in line with the fact that miR-34a is a MYCN negative regulator [37]. miR-34a is also proficient to induce a cell cycle arrest and subsequent caspase dependent apoptosis through BCL2 [36] [37], E2F3 [35] and SIRT1 repression[38]. In addition, analysis of the transcriptome induced by miR-34 overexpression exhibits high similarity with that observed with p53 induction, being highly enriched for genes regulating cell-cycle progression, apoptosis, DNA repair and angiogenesis [39] [40**] [41**]. Indeed, miR-34 family members are direct transcriptional targets of p53 (for a review see [42]) and are essential for the correct execution of p53-dependent cellular responses. However, it should be considered that miR-34a pro-apoptotic effects seem to be cell type dependent; in fact, miR-34a was proven to increase in stress-induced renal carcinogenesis rat model, and its inhibition was proven to affect tumor cell proliferation [43].

miRNAs can also act upstream of p53. For example, miR-127, a miRNA epigenetically silenced in tumors, represses the proto-oncogene BCL6 [44] [45], a p53 negative regulator, well known for being up-regulated in lymphoproliferative disorders. In addition, miRNAs can act as regulators signaling downstream of TP53. In fact, miR-155 is responsible for silencing TP53 functions by directly repressing TP53INP1[46], an important mediator of TP53 antioxidant and proapoptotic activities[47].

Other major pro-apoptotic miRNAs with reduced expression in tumors include miR-15a/16-1 cluster that repress the anti-apoptotic BCL2 protein and activate the intrinsic apoptotic program APAF-1-CASPASE-9-PARP[48], and miR-101, that among other important targets, such as the methyltransferase EZH2[49], also silences the survival BCL2 homologues protein MCL1[50].

4) LIMITLESS REPLICATIVE POTENTIAL. Cellular senescence is a physiological withdrawal from the cell cycle in response to a multitude of different stress stimuli, including oncogene activation, and involving telomerase deregulation. MiRNA relevance to oncogene induced premature senescence has been addressed with a genetic miRNA-screening library: miR-373 and miR-372 were identified as capable of allowing transformation of primary cells harboring oncogenic RAS and wild-type p53, by neutralizing p53 mediated CDK inhibition through suppression of LATS2 [51].

miR-138 and telomerase expression levels have been found inversely correlated in both anaplastic and papillary thyroid carcinoma [52] and the mechanistic explanation is through reduction of miR-138 expression levels in tumors, which can repress TERT mRNA translation inducing consequent telomerase deregulation.

In the avenue toward senescence, p53 activated miRNAs are also important: it has been proven that the miR-34 family participates to the senescence program [53], through modulation, at least for miR-34a, of the E2F signaling pathway [54]. Furthermore, 15 miRNAs were found downregulated in senescent cells and in breast cancers harboring wild-type p53 and proved that these miRNAs are repressed by p53 in an E2F1-mediated manner [55].

5) ANGIOGENESIS. Tumor cells turn on the “angiogenic switchâ€Â to produce high amounts of pro-angiogenic factors and promote neovascularization. The most important angiogenic factor, VEGF, is highly expressed in most tumors, both solid and hematologic, and proven to be induced by hypoxia. In tumor progression hypoxia has been found to contribute to the modulation of miRNA expression, partly by direct HIF-1 transcriptional activation of specific miRNAs [56]. These miRNAs have dual functions: on one hand they participate in the angiogenic process, and on the other they aid the cell in engaging anti-apoptotic programs sustaining cell survival (e.g. miR-26, miR-107 and miR-210 inhibit caspase 3 activation). For example, miR-27a by restraining the zinc finger gene ZBTB10, a negative regulator of the Specificities Protein (SP) transcription factors, induces SP dependent transcription of both survival and angiogenic genes (i.e. survivin, VEGF, VEGFR) [57]. Furthermore, miR-210, through direct modulation of the tyrosine kinase receptor ligand Ephrin A, represents a component of the circuitry controlling endothelial cell chemotaxis and tubuligenesis [58]. Recently, it has been shown that VEGF is also restrained at the post-transcriptional level by miRNAs. On one hand, miR-126 was found to directly repress in in vitro and in vivo lung cancer cell models VEGF-A expression and to induce a G1 cell cycle arrest with an overall reduction of tumor volume [59]. On the other hand, miR-126 expression was found to be enriched in endothelial cells during angiogenesis and to repress negative regulators of the VEGF pathway (SPRED1 and PIK3R2) [60,61], therefore exerting opposite roles according to cell context. miRNAs downregulated in hypoxic conditions, such as miR-16, miR-15b, miR-20a and miR-20b are able to directly modulate VEGF expression levels as well. This creates a positive feed-forward loop in which hypoxic repressed miRNAs reinforce the expression levels of a potent pro-angiogenic hypoxic induced growth factor, as VEGF [62].

6) INVASION AND METASTASIS. The metastatic process starts with the acquisition of an invasive behavior that allows cells to detach from the primary tumor, enter the blood or lymphatic vasculature and spread to distant organs. It was revealed that up-regulation of miR-10b promotes invasion and metastasis. Twist, a metastasis-promoting transcription factor, could induce miR-10b expression, whereas HOXD10, a homeobox transcription factor that promotes or maintains a differentiated phenotype in epithelial cells, was shown to be a target of miR-10b being expressed at low level in metastatic tumors. Consequently, RhoC, a G-protein involved in metastasis that is repressed by HOXD10, becomes strongly expressed in response to miR-10b expression [63**].

Distinct lines of evidence revealed that miR-373 and miR-520c are also metastasis-promoting miRNAs. Their pro-invasive and pro-migratory effect was initially studied in in vitro and in vivo breast cancer models and explained via direct suppression of CD44. CD44 encodes a cell surface receptor for hyaluronan, [64**] and is consistently reduced in metastatic breast, colon and prostate cancer. The pro-invasive function of miR-373/520c via CD44 regulation have been further confirmed in a prostate cancer model[65].

MiRNAs can also be metastasis-suppressors, as it was first revealed for miR-335, miR-126 and miR-206. Clinically, the low expression of miR-335 or miR-126 was significantly associated with poor metastasis-free survival. Experimentally, the knockdown of SOX4 and tenascin C (TNC) diminished in vitro invasive ability and in vivo metastatic potential, indicating these genes as critical effectors of metastasis activated by the loss of miR-335 [66**].

miR-21, besides controlling cell survival and proliferation is also a mastor regulator of the metastatic process by directly modeling the cell cytoskeleton via TPM1 suppression[67][68], and by indirectly regulating the expression of the pro-metastatic UPAR (via maspin and PDCD4 direct suppression)[68] and of matrix metalloproteinases (via RECK,TIMP3 [69] and PTEN [70] direct suppression)

Interestingly, the pleiothropic putative tumorsuppressor miR-34a in addition to repressing genes involved in G1 arrest, apoptosis and senescence has been shown to participate in the regulation of tumor cell scattering, migration, and invasion via downregulation of c-MET and its downstream signaling cascades[71].

All the members of the miR-200 family together with miR-205 were found significantly down-modulated during the Epithelial-mesenchymal transition (EMT) (for a review see [72]), a developmental process through which cells loosen their cell-cell and cell-matrix contacts and switch from a collective invasion pattern to a detached and disseminated cell migration method. These miRNAs are able to regulate the expression of key mediators (i.e. TGFB1 and ZEB1/2) involved in the EMT and tumor metastasis. Recent observations demonstrated that not only miR-200 family regulates ZEB1/2 expression, but also ZEB1 regulates miR-200 family transcription [73**,74**], thus establishing a complex regulatory loop that may ensure the tight control of the EMT process.

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