Emerging evidence demonstrates that both tumor suppressor and oncogenic miRNAs play an essential role in stem cell self-renewal and differentiation by negatively regulating the expression of certain key genes in stem cells. It seems logical that they may also be critical players in cancer stem cells. Though small in size, miRNAs play a key role in the epigenetic regulation of cancer stem cells. Specifically, the imbalance of oncogenic vs. tumor suppressor miRNAs may lead to dysregulation of cancer stem cells, thus causing excessive self-renewal and survival of cancer stem cells, and resistance to chemo/radiotherapy. We postulate that restoring the balance of miRNAs will correct this dysregulation via the direct and simultaneous modulation of downstream stem cell pathways involved in cancer stem cell self-renewal and/or differentiation. The resultant restoration of key regulatory pathways could improve therapeutic response. Restoring tumor suppressor miRNAs and/or inhibiting oncogenic miRNAs may provide a novel molecular therapy for human cancers, potentially via modulating cancer stem cells

Hao, Ping

Ji, Qing

Karnak, David

Wang, Rongquan

Xu, Liang

PubMed

This is the published version, also available here: http://www.ijcem.com/1002003A.html.Emerging evidence demonstrates that both tumor suppressor and oncogenic miRNAs play an essential role in stem cell
self-renewal and differentiation by negatively regulating the expression of certain key genes in stem cells. It seems logical that they may also be critical players in cancer stem cells.  Though small in size, miRNAs play a key role in the epigenetic regulation of cancer stem cells. Specifically, the imbalance of oncogenic vs. tumor suppressor miRNAs may lead to dysregulation of cancer stem cells, thus causing excessive self-renewal and survival of cancer stem cells, and resistance to chemo/radiotherapy.  We postulate that restoring the balance of miRNAs will correct this dysregulation via the direct and simultaneous modulation of downstream stem cell pathways involved in cancer stem cell self-renewal and/or differentiation.  The resultant restoration of key regulatory pathways could improve therapeutic response.  Restoring tumor suppressor miRNAs and/or inhibiting oncogenic miRNAs may provide a novel molecular therapy for human cancers, potentially via modulating cancer stem cells. (IJCEM1002003)

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  Introduction  Tumor recurrence accompanied by resistance to treatment, i.e., the tumors respond to initial therapies but eventually re-emerge and become resistant to chemo/radiotherapy, remains a daunting clinical challenge. Recent studies sug-gest that the drug-resistance of recurring tu-mors may be due to a special small sub-population of the malignancy named tumor-initiating cells or cancer stem cells [1]. Cancer stem cells are thought to comprise only a frac-tion of the tumor and maintain self-renewal, unlimited growth and differentiation capabili-ties. These attributes make them responsible for tumor outgrowth, progression, drug-resistance and metastasis [2].   Existing knowledge about the hierarchical role of non-malignant stem cells in tissue mainte-nance has driven much of the research into cancer stem cell biology. Adult stem cells are found in numerous tissues of the body and play a role in tissue development, replacement and repair [3]. Breast stem cells exhibit the two hall-marks of stem cells, multipotency and self-renewal. It has been shown that a single cell enriched with certain cell surface markers has the ability to grow a fully functional mammary gland in vivo [1, 4]. Similarly, a single cancer stem cell will establish a new tumor that dis-plays the same heterogeneity of surface mark-ers found in the tumor from whence it came. The cancer stem cell hypothesis arose from ob-servations in haematopoietic malignancies but has since expanded to solid tumors. By using in vitro culture techniques and in vivo transplant models, investigators have established evi-dence of cancer stem cells in colon, pancreas, prostate, brain and breast cancers [4-12]. The prevailing view is that cancer stem cells are a small sub-population of cells capable of self-renewal and differentiation, although in some types of human cancers such as melanoma, Int J Clin Exp Med 2010;3(1):84-87 www.ijcem.com /IJCEM1002003  Medical Hypothesis  No small matter: microRNAs -- key regulators of cancer stem cells  Qing Ji1,3, David Karnak3, Ping Hao2, Rongquan Wang1, and Liang Xu3  1Department of Digestive Diseases, The First Affiliated Hospital, 2Department of Oncology, The Second Affiliated Hos-pital, Third Military Medical University, Chongqing 400038, China; 3Department of Radiation Oncology, Comprehen-sive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.  Received February 5, 2010, accepted March 5, 2010, available online March 12, 2010  Abstract:  Emerging evidence demonstrates that both tumor suppressor and oncogenic miRNAs play an essential role in stem cell self-renewal and differentiation by negatively regulating the expression of certain key genes in stem cells. It seems logical that they may also be critical players in cancer stem cells. Though small in size, miRNAs play a key role in the epigenetic regulation of cancer stem cells. Specifically, the imbalance of oncogenic vs. tumor suppressor miRNAs may lead to dysregulation of cancer stem cells, thus causing excessive self-renewal and survival of cancer stem cells, and resistance to chemo/radiotherapy. We postulate that restoring the balance of miRNAs will correct this dysregulation via the direct and simultaneous modulation of downstream stem cell pathways involved in cancer stem cell self-renewal and/or differentiation. The resultant restoration of key regulatory pathways could improve therapeu-tic response. Restoring tumor suppressor miRNAs and/or inhibiting oncogenic miRNAs may provide a novel molecular therapy for human cancers, potentially via modulating cancer stem cells.  Keywords: microRNAs, stem cells, cancer, regulators, oncogene microRNAs and cancer stem cells   85                                                                                                             Int J Clin Exp Med 2010; 3(1):84-87 such tumorigenic cells may not be rare [13]. To be maximally effective, cancer therapy must be directed against both the largely quiescent pool of cancer stem cells as well as the more actively proliferating bulk tumor cells [14]. This may be possible if specific stem cell signals are inhib-ited using molecularly targeted therapy, while at the same time attacking proliferating cells by conventional means [15, 16]. To achieve this goal, developments in microRNA regulation pre-sent exciting prospects.    MicroRNAs (miRNAs) are a conserved class of naturally occurring 20-22nt non-coding RNAs that regulate gene expression by binding to mRNA, leading to mRNA degradation or transla-tional inhibition [17]. Our group recently re-viewed miRNA biogenesis and outlined how the majority of miRNAs achieve specificity and acti-vate the RNA interference pathway by 6-8 com-plementary base pair interactions with the 3’ UTRs of their targets [18]. By this mechanism, they can regulate a variety of biological proc-esses, including developmental timing, signal transduction, tissue differentiation and mainte-nance, disease (for an interesting analysis of miRNA and disease processes see [19]), and carcinogenesis [17]. Indeed, multiple miRNAs have been reported as either oncogenes or tu-mor suppressors. Emerging evidence demon-strates that miRNAs play an essential role in stem cell self-renewal and differentiation by negatively regulating the expression of certain key genes in stem cells [17]. One study has shown that microRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas [20]. mi-R21 itself is an oncogene that is overexpressed in certain breast cancers and can affect tumorigenesis through modulating key players in apoptotic control including the proto-oncogene Bcl-2 [21-23]. Other miRNAs, such as miR-15 and miR-16, have been reported to downregulate Bcl-2. Their deletion in cancer allows for apoptosis inhibition when Bcl-2 is subsequently expressed at high levels [24, 25]. The obstacle to apop-tosis due to overexpression of Bcl-2 results in an increased number of stem cells in vivo [26]. This suggests that apoptosis plays a role in regulating the microenvironments of stem cells [27].   We recently demonstrated that miR-34 plays an important role in the p53 tumor suppressor net-work.  Restoration of miR-34 reestablishes the tumor-suppressing signaling pathway in human gastric and pancreatic cancer cells lacking func-tional p53 [28, 29]. As a result, miR-34 potently inhibits tumorsphere formation and growth in p53-mutant human gastric cancer cells, provid-ing the first proof-of-concept that there is a po-tential link between the tumor suppressor miR-34 and cancer cell self-renewal [28]. In a differ-ent model system, we recently reported that miR-34 inhibits CD44+/CD133+ pancreatic cancer stem cells self-renewal in vitro and tu-mor-initiation in vivo [29]. The mechanism of miR-34-mediated suppression of gastric and pancreatic cancer stem cell self-renewal might be related to the direct modulation of down-stream targets Bcl-2 and Notch, implying that miR-34 may be involved in cancer stem cell self-renewal / differentiation decision-making [18, 29]. Our data suggest that miR-34 may hold significant promise as a new class of molecular therapy for human gastric and pancreatic can-cer, potentially by modulating cancer stem cells.   Discussion and Future Directions  miRNAs regulate a variety of biological proc-esses, including developmental timing, signal transduction, tissue differentiation and mainte-nance, disease, and carcinogenesis [17, 30]. Altered expression of specific miRNA genes con-tributes to the initiation and progression of can-cer [30]. Disruption of miRNA expression levels in tumor cells may result from distorted epige-netic regulation of miRNA expression, abnor-malities in miRNA processing genes or proteins, and the location of miRNAs at cancer-associated genomic regions [31]. Clearly, miRNAs play a critical role in carcinogenesis as well as tumor progression [18, 32]. Certain ab-normal miRNA expression levels cause cancer stem cell dysregulation, resulting in unlimited self-renewal and cancer progression [30, 33]. Therefore, microRNA expression is a vital key to cancer stem cell dysregulation [18]. In addition, a number of miRNAs have been identified within cancers to function as either oncogenes or tu-mor suppressors [34, 35]. Silber et al. reported that miR-124 and miR-137 induce differentia-tion of neural stem cells and glioblastoma stem cells and induce glioblastoma cell cycle arrest [36]. These results suggest that the targeted delivery of miR-124 and miR-137 to glioblas-toma cells may be therapeutically efficacious for the treatment of this disease [36]. Another re-microRNAs and cancer stem cells   86                                                                                                             Int J Clin Exp Med 2010; 3(1):84-87 cent study shows that miRNA Let-7 regulates self-renewal of breast cancer stem cells [33]. These miRNAs offer great promise for cancer therapy because they might have potential to regulate aberrant miRNA expression in cancer stem cells [18]. Thus miRNA therapy could be a powerful tool to correct the cancer stem cell dysregulation and its resulting excessive self-renewal and cancer progression in patients.   We have demonstrated the importance of miR-34 and its relation to the p53 tumor suppressor network and cancer stem cells [18, 28, 29]. miR-34 targets Notch, cMET, HMGA2 and Bcl-2, genes involved in the self-renewal and survival of cancer stem cells, suggesting a potential role of miR-34 in cancer stem cells [18]. Restoration of miR-34 was able to re-establish the tumor suppressing signaling pathway in cancer cells lacking functional p53. More significantly, miR-34 can inhibit cancer cell growth and tumor initiation via inhibiting the self-renewal of can-cer stem cells. This indicates that miR-34 can function as a tumor suppressor gene in p53-deficient cancer cells and that its loss-of-function plays a role in the dysregulated self-renewal in cancer stem cells [29]. More impor-tantly, miR-34 restoration led to an 87% reduc-tion of the CD44+/CD133+ tumor initiating cells (cancer stem cells), accompanied by significant inhibition of tumorsphere growth and tumor initiation in vivo [29].  If our hypothesis holds true, miRNAs like miR-34 may play an important role in cancer stem cell self-renewal / differentiation processes. Deline-ating the role of miR-34 in regulation of cell growth and tumor progression, and its relation-ship with cancer stem cells, will help us better understand the p53 tumor suppressor signaling network, facilitate our research in carcinogene-sis and cancer therapy, and build a solid foun-dation for our exploration of novel strategies in diagnosis, treatment and prevention of cancer.  Modulating cancer stem cell signaling pathways to improve chemotherapeutic response is an exciting new avenue for molecularly targeted therapy. The restoration of tumor suppressor miRNAs and/or inhibition of oncogenic miRNAs provide novel prospects for clinical innovation.   Acknowledgements  This work was supported in part by China TMMU Natural Science Foundation (2009XHG10) and Chongqing Natural Science Foundation (CSTC, 2009BB5022) (to Q. J.), and United States NIH grants R01 CA121830(S1) and R01 CA134655 (to L. X.).    Please address correspondence to:  Qing Ji, MD, PhD, Department of Digestive Diseases, The First Affiliated Hospital, Third Military Medical University, Chongqing 400038, China. Tel: 86-13500380255, E-mail: qingji@hotmail.com; Or: Liang Xu, MD, PhD, Depart-ment of Radiation Oncology, Division of Cancer Biol-ogy, University of Michigan, 4424E Med Sci I, 1301 Catherine St., Ann Arbor, MI 48109-5637, Tel: 734-615-7017, Fax: 734-615-3422, E-mail: li-angxu@umich.edu   References  [1] Al-Hajj M and Clarke MF. Self-renewal and solid tumor stem cells. Oncogene 2004; 23: 7274-7282. [2] Wicha MS. Breast cancer stem cells: the other side of the story. Stem Cell Rev 2007; 3: 110-112; discussion 113. [3] Farnie G and Clarke RB. Mammary stem cells and breast cancer--role of Notch signalling. Stem Cell Rev 2007; 3: 169-175. [4] Dontu G, Al-Hajj M, Abdallah WM, Clarke MF and Wicha MS. Stem cells in normal breast develop-ment and breast cancer. Cell Prolif 2003; 36 Suppl 1: 59-72. [5] Yi SY and Nan KJ. Tumor-initiating stem cells in liver cancer. Cancer Biol Ther 2008; 7: 325-330. [6] Peacock CD and Watkins DN. Cancer stem cells and the ontogeny of lung cancer. J Clin Oncol 2008; 26: 2883-2889. [7] Tang DG, Patrawala L, Calhoun T, Bhatia B, Choy G, Schneider-Broussard R and Jeter C. Prostate cancer stem/progenitor cells: identification, characterization, and implications. Mol Carcinog 2007; 46: 1-14. [8] Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF and Ailles LE. Identification of a subpopula-tion of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A 2007; 104: 973-978. [9] Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF and Simeone DM. Identification of pancreatic cancer stem cells. Cancer Res 2007; 67: 1030-1037. [10] Collins AT, Berry PA, Hyde C, Stower MJ and Maitland NJ. Prospective identification of tumori-genic prostate cancer stem cells. Cancer Res 2005; 65: 10946-10951. [11] Clarke MF. A self-renewal assay for cancer stem cells. Cancer Chemother Pharmacol 2005; 56 Suppl 1: 64-68. [12] Al-Hajj M, Wicha MS, Benito-Hernandez A, Morri-son SJ and Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl microRNAs and cancer stem cells   87                                                                                                             Int J Clin Exp Med 2010; 3(1):84-87 Acad Sci U S A 2003; 100: 3983-3988. [13] Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM and Morrison SJ. Efficient tumour formation by single human melanoma cells. Nature 2008; 456: 593-598. [14] Rich JN. Cancer stem cells in radiation resis-tance. Cancer Res 2007; 67: 8980-8984. [15] Al-Hajj M. Cancer stem cells and oncology thera-peutics. Curr Opin Oncol 2007; 19: 61-64. [16] Wicha MS. Cancer stem cells and metastasis: lethal seeds. Clin Cancer Res 2006; 12: 5606-5607. [17] Hatfield S and Ruohola-Baker H. microRNA and stem cell function. Cell Tissue Res 2008; 331: 57-66. [18] Desano JT and Xu L. MicroRNA Regulation of Cancer Stem Cells and Therapeutic Implications. AAPS J 2009;  [19] Lu M, Zhang Q, Deng M, Miao J, Guo Y, Gao W and Cui Q. An analysis of human microRNA and disease associations. PLoS One 2008; 3: e3420. [20] Corsten MF, Miranda R, Kasmieh R, Krichevsky AM, Weissleder R and Shah K. MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural pre-cursor cell delivered S-TRAIL in human gliomas. Cancer Res 2007; 67: 8994-9000. [21] Frankel LB, Christoffersen NR, Jacobsen A, Lin-dow M, Krogh A and Lund AH. Programmed Cell Death 4 (PDCD4) Is an Important Functional Target of the MicroRNA miR-21 in Breast Cancer Cells. J Biol Chem 2008; 283: 1026-1033. [22] Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S and Allgayer H. MicroRNA-21 (miR-21) post-transcriptionally downregu-lates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colo-rectal cancer. Oncogene 2008; 27: 2128-2136. [23] Si ML, Zhu S, Wu H, Lu Z, Wu F and Mo YY. miR-21-mediated tumor growth. Oncogene 2007; 26: 2799-2803. [24] Tarasov V, Jung P, Verdoodt B, Lodygin D, Epan-chintsev A, Menssen A, Meister G and Her-meking H. Differential regulation of microRNAs by p53 revealed by massively parallel sequenc-ing: miR-34a is a p53 target that induces apop-tosis and G1-arrest. Cell Cycle 2007; 6: 1586-1593. [25] Cho WC. OncomiRs: the discovery and progress of microRNAs in cancers. Mol Cancer 2007; 6: 60. [26] Domen J, Gandy KL and Weissman IL. Systemic overexpression of BCL-2 in the hematopoietic system protects transgenic mice from the conse-quences of lethal irradiation. Blood 1998; 91: 2272-2282. [27] Domen J, Cheshier SH and Weissman IL. The role of apoptosis in the regulation of hematopoi-etic stem cells: Overexpression of Bcl-2 in-creases both their number and repopulation potential. J Exp Med 2000; 191: 253-264. [28] Ji Q, Hao X, Meng Y, Zhang M, Desano J, Fan D and Xu L. Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres. BMC Cancer 2008; 8: 266. [29] Ji Q, Hao X, Zhang M, Tang W, Yang M, Li L, Xiang D, Desano JT, Bommer GT, Fan D, Fearon ER, Lawrence TS and Xu L. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One 2009; 4: e6816. [30] Croce CM and Calin GA. miRNAs, cancer, and stem cell division. Cell 2005; 122: 6-7. [31] Calin GA and Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6: 857-866. [32] Papagiannakopoulos T and Kosik KS. MicroR-NAs: regulators of oncogenesis and stemness. BMC Med 2008; 6: 15. [33] Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J and Song E. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007; 131: 1109-1123. [34] Lowery AJ, Miller N, McNeill RE and Kerin MJ. MicroRNAs as prognostic indicators and thera-peutic targets: potential effect on breast cancer management. Clin Cancer Res 2008; 14: 360-365. [35] Wiemer EA. The role of microRNAs in cancer: no small matter. Eur J Cancer 2007; 43: 1529-1544. [36] Silber J, Lim DA, Petritsch C, Persson AI, Mau-nakea AK, Yu M, Vandenberg SR, Ginzinger DG, James CD, Costello JF, Bergers G, Weiss WA, Alvarez-Buylla A and Hodgson JG. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 2008; 6: 14.  

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No small matter: microRNAs -- key regulators of cancer stem cells

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No small matter: microRNAs – key regulators of cancer stem cells

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