Targeting oncomiRNAs and mimicking tumor suppressor miRNAs: New trends in the development of miRNA therapeutic strategies in oncology (Review)

Since the introduction of high-dose chemotherapy about 35 years ago, survival rates of osteosarcoma patients have not been significantly improved. New therapeutic strategies replacing or complementing conventional chemotherapy are therefore urgently required. MicroRNAs represent promising targets for such new therapies, as they are involved in the pathology of multiple types of cancer, and aberrant expression of several miRNAs has already been shown in osteosarcoma. In this study, we identified silencing of miR-127-3p and miR-376a-3p in osteosarcoma cell lines and tissues and investigated their role as potential tumor suppressors in vitro and in vivo. Transfection of osteosarcoma cells (n = 6) with miR-127-3p and miR-376a-3p mimics significantly inhibited proliferation and reduced the colony formation capacity of these cells. In contrast, we could not detect any influence of miRNA restoration on cell cycle and apoptosis induction. The effects of candidate miRNA restoration on tumor engraftment and growth in vivo were analyzed using a chicken chorioallantoic membrane (CAM) assay. Cells transfected with mir-127-3p and miR-376a-3p showed reduced tumor take rates and tumor volumes and a significant decrease of the cumulative tumor volumes to 41% and 54% compared to wildtype cells. The observed tumor suppressor function of both analyzed miRNAs indicates these miRNAs as potentially valuable targets for the development of new therapeutic strategies for the treatment of osteosarcoma.

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The guardians of the genome dependent tumor suppressor miRNAs network

Nature Precedings ◽

10.1038/npre.2009.4112.1 ◽

2009 ◽

Cited By ~ 1

Author(s):

Lakshmanane Boominathan

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Mirnas

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Alive failures behind the windows of cancer therapy

International Journal of Medicine ◽

10.14419/ijm.v5i2.7035 ◽

2017 ◽

Vol 5 (2) ◽

pp. 179

Author(s):

Muhammad Islam

Keyword(s):

Cancer Therapy ◽

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Therapeutic Strategies ◽

Cancer Therapies ◽

Physiological System ◽

Suppressor Genes ◽

Immune Therapies

The multiscope process, cancer is attributable from various geneses. Eventually, cancer is a complicated disease with unconstrained interca-lation and impacts on the physiological system. Therefore, an ideal cancer therapy must be like a multi-edged sword. Broadly, currently, available cancer therapies are the cytoprotective, inhibitors of oncogenes, correctors, and cell destructors. Doubtless, cancer therapists are most frequently handling apoptosis and autophagy inducers, targeting of tumor suppressor genes, epigenetic and immune therapies. How-ever, each therapy has a number of challenges yet to be resolved. This revision is aimed to find out some important points, depicting till the date, how successful we are and what are the failures behind those modes of therapeutic strategies.

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Abstract 2107: Deregulation of tumor suppressor miRNAs results in Six1 oncogene overexpression in pediatric and adult human cancers

10.1158/1538-7445.am10-2107 ◽

2010 ◽

Author(s):

J. Saadi Imam ◽

Kalyan Buddavarapu ◽

Jennifer S. Lee-Chang ◽

Peter Hornsby ◽

Yidong Chen ◽

...

Keyword(s):

Tumor Suppressor ◽

Adult Human ◽

Human Cancers ◽

Tumor Suppressor Mirnas

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Comparison of miRNA Expression Profiles in Leukemia-Derived Microvesicles and Corresponding Leukemia Cells and Analysis of Their Roles in Leukemia

Blood ◽

10.1182/blood.v118.21.1388.1388 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1388-1388

Author(s):

Xiaomei Chen ◽

Fang Liu ◽

Wei Xiong ◽

Xiangjun Chen ◽

Cong Lu ◽

...

Keyword(s):

Tumor Suppressor ◽

Mirna Expression ◽

Tumor Suppressors ◽

Target Genes ◽

Expression Profiles ◽

K562 Cells ◽

Cell Types ◽

Leukemic Cells ◽

Mirna Expression Profiles ◽

Tumor Suppressor Mirnas

Abstract Abstract 1388 Microvesicles(MVs) are small exosomes of endocytic origin released by normal healthy or damaged cell types, including leukemic cells. MVs have been considered as cell dust, however, recent data bring evidences that MVs generated during cell activation or apoptosis can transfer biologic messages between different cell types. MicroRNAs (miRNAs) have been demonstrated to be aberrantly expressed in leukemia and the overall miRNA expression could differentiate normal versus leukemia. The MVs expressing miRNAs were found in the primary tumors. However it is currently unknown whether miRNA content changes in MVs derived from leukemic cells. Here we compared the miRNA expression in leukemia-derived MVs to corresponding leukemia cells and analysed their roles in leukemia. K562 cells were cultured and collected. MVs derived from K562 cells were also isolated. The presence and levels of specific miRNAs from both MVs derived from K562 cells and K562 cells were determined by Agilent miRNA microarray analysis probing for 888 miRNAs. Some selected miRNAs were verified by real time qRT-PCR. Bioinformatic software tools were used to predict the target genes of identified miRNAs and define their function. Our results showed that 77 and 122 miRNAs were only expressed in MVs and K562 cells, respectively. There were significant differences in miRNA expression profiles between MVs and K562 cells. We also found that 112 miRNAs were co-expressed in MVs and K562 cells. This observaton may suggest that compartmentalization of miRNAs from cells into to MVs, for at least some miRNAs, is an active (selective) process. Among those abnormally expressed miRNAs, some have been proposed oncomiRNAs or tumor suppressors. For example, miR-155, has been proposed as oncomiRNA, was abnormally expressed only in MVs in our study, suggesting that oncomiRNA was present in MVs. Further analysis revealed that 39 potential target genes regulated by miR-155. Among them, 4 genes involed in oncogenes and the signal genes. OncomiRNAs such as miR-27a and miR-21 expressed in both MVs and corresponding cells, indicating that MVs bear miRNA characteristic of the cell origin. MVs, released into the leukemia microenvironment, play an important role in leukemia. In contrast to oncomiRNAs, if miRNA is associated with tumor suppressive activity, it is regarded as a tumor suppressor (oncosuppressor). The aberrantly expressed miR-125a-3p, miR-125-5p,miR-27b, which have implicated as tumor suppressors, appear in both cellular and MVs of leukemia in our study. MiR-125a-3p, miR-125-5p and miR-27b regulated 308 potential target genes. To our knowledge, 10 of them are tumor suppression genes. It is possible that these aberrantly expressed tumor suppressor miRNAs decreased or lost their roles of tumor suppression, which led to decrease or loss their roles of regulating their target genes including oncogenes, consequently resulted in leukemia. Since K562 cells presented t(9;22), we further examined the predicted function of the 6 expressed miRNAs located in chrosome 9 (hsa-miR-188-5p,hsa-miR-602)and 22(hsa-let-7b,hsa-miR-1249,hsa-miR-130b,hsa-miR-185), which expressed both in the MVs and K562 cells. Using the TargetScan, we found 442 predicted targets regulated by 6 miRNAs. Those miRNAs may play roles in leukemia via these 422 genes. This study is the first to identify and define miRNA expression between K562 cells presented t(9;22), derived from K562 cells and their corresponding cells. We found significant differences in miRNA expression between MVs and corresponding leukemia. K562 cells released MVs riched in miRNAs including oncomiRNAs or tumor suppressor miRNAs into leukemia microenvironment, which play a role in leukemia via regulating their targer genes including oncogenes, consequently resulted in leukemia. Disclosures: No relevant conflicts of interest to declare.

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The guardians of the genome dependent tumor suppressor miRNAs network

Nature Precedings ◽

10.1038/npre.2009.4112 ◽

2009 ◽

Author(s):

Lakshmanane Boominathan ◽

Lakshmanane Boominathan

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Mirnas

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The Mir-193 Family Antagonizes Stem Cell Pathways and Is a Potent Tumor Suppressor in Childhood and Adult Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.1244.1244 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1244-1244

Author(s):

Kathrin Krowiorz ◽

Razan Jammal ◽

Stephan Emmrich ◽

Arefeh Rouhi ◽

Michael Heuser ◽

...

Keyword(s):

Cell Cycle ◽

Bone Marrow ◽

Stem Cell ◽

Tumor Suppressor ◽

Cell Lines ◽

Family Members ◽

S Phase ◽

The Impact ◽

Tumor Suppressor Mirnas ◽

Acute Myeloid

Abstract MicroRNAs (miRNAs) are essential for maintenance and differentiation of normal hematopoietic cells and their dysregulation is strongly implicated in leukemias. In order to identify tumor suppressor miRNAs in the context of hematological malignancies, we performed two complementary miRNA expression screenings in normal hematopoiesis as well as in childhood and adult acute myeloid leukemias (AML). We reasoned that tumor suppressor miRNAs are upregulated in mature myeloid cells, as compared to normal hematopoietic stem and progenitor cells (HSPCs), and downregulated in AML. Based on this screening strategy, we identified the miR-193 family members as potent suppressors of HSPC activity and AML growth. During normal hematopoiesis mmu-miR-193a-3p is exclusively expressed in mature myeloid cells and absent in normal HSPCs. Accordingly, in a cohort of 165 pediatric AML patients hsa-miR-193b-3p was broadly repressed throughout the cytogenetically characterized subgroups. In addition, in a cohort of 43 adult AML patients, its homolog hsa-miR-193a-3p was significantly upregulated in APL cases (p=0.0025, n=7) compared to bone marrow from healthy donors (n=5). To assess the impact of the miR-193 family members on AML maintenance and development, we lentivirally expressed miR-193a/b in the MLL-rearranged cell lines ML2 and THP1, which induced monocytic differentiation in concert with calcitriol treatment, measured by CD11b/CD14 expression (p=0.024). Consistently, enforced miR-193-expression led to a significant growth disadvantage in ML2 and THP1 cells (p=<0.001 and p=0.02, respectively) as well as to reduced colony formation (p=0.008) in methylcellulose-based colony-forming unit (CFU) assays. Noteworthy, these effects were not restricted to MLL-rearranged AML cell lines only, but were also evident in six other AML cell lines representing the most common AML subgroups, such as t(8;21) and t(15;17). Beyond the growth-suppressive and differentiation-inductive effect of miR-193 in human AML cell lines, overexpression of miR-193a caused a significant decrease of proliferation in murine bone marrow cells immortalized in vitro by retroviral expression of Hoxa9 or Hoxa9 and Meis1 (p=0.019 and p=0.008, respectively). Based on these findings in AML, we further investigated the impact of the miR-193 family on normal hematopoiesis. We retrovirally expressed miR-193a in 32D cells treated with granulocyte-colony stimulating factor (G-CSF), which resulted in a strong induction of myeloid differentiation already after day 2 (p=0.006) as assessed by CD11b/Gr-1 surface marker expression. We lentivirally transduced mouse lineage negative (Lin-) HSPCs and transplanted them into irradiated isogenic recipients. Bleedings performed on weeks 4, 8 and 11, as well as the examination of the bone marrow on week 11, showed a severe competitive disadvantage of miR-193-transduced cells (week 11: 2% GFP+ miR-193- vs. 25% GFP+ miR-NSC-transduced cells). These results were further refined using highly purified ESLAM (CD45+ EPCR+ CD48− CD150+) HSCs which failed to reconstitute hematopoiesis when overexpressing miR-193a, indicated by the absence of miR-193a/GFP+ cells at week 8 post transplantation. These observations might be explained by a potent G1 cell cycle arrest in HSPCs when overexpressing miR-193a/b (4-fold decrease in the S phase population) and induction of apoptosis. Our results in normal and malignant hematopoiesis suggested that the miR-193 family acts globally through targeting relevant stem cell pathways. To validate this hypothesis we quantified the knockdown of ten predicted miR-193 target genes. qRT-PCR analysis confirmed the down regulation of KIT, KRAS, SOS2 (key components of the MAPK signaling pathway) and CCND1, a CDK regulator of G1/S phase transition. We propose a dual regulatory platform where firstly, miR-193 targets CCND1 and controls the cell cycle kinetics of stem cells. Secondly, miR-193 interferes with the KIT proto-oncogene and the RAS pathway thereby inhibiting crucial pro-proliferation and anti-apoptotic signaling cascades. Taken together, we identified the miR-193 family as a pan-tumor suppressor in childhood and adult AML. Its anti-leukemic effect is mediated by targeting the stem cell KIT/SOS2/RAS/RAF axis. Disclosures No relevant conflicts of interest to declare.

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Prognostic Value of Mutations in TP53 and RAS Genes in Breast Cancer

The International Journal of Biological Markers ◽

10.1177/172460080301800108 ◽

2003 ◽

Vol 18 (1) ◽

pp. 49-53 ◽

Cited By ~ 4

Author(s):

E. Guerra ◽

G. Vacca ◽

B. Palombo ◽

S. Alberti

Keyword(s):

Breast Cancer ◽

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Statistical Power ◽

Healthcare Systems ◽

Therapeutic Strategies ◽

Response To Therapy ◽

Suppressor Genes ◽

Ras Genes ◽

Molecular Indicators

The identification of molecular indicators of higher risk for specific subgroups of cancer patients may allow to develop more aggressive therapeutic strategies aimed at cases with the highest likelihood of response. This would avoid unnecessary toxicity to patients and alleviate the burden of cancer care for healthcare systems. Activated oncogenes and mutated tumor suppressor genes are causal determinants of the appearance and progression of tumors in man. They therefore represent potential indicators of prognosis and/or response to therapy. However, even in cases of well-studied oncogenes and tumor suppressor genes such as TP53 and RAS, their attributed prognostic and predictive value is often based on studies of insufficient statistical power that often lead to conflicting conclusions. Findings in favor or against the use of TP53 and RAS as prognostic and predictive indicators in breast cancer are reviewed and discussed here.

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