miRNAs in Cancer: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Pathology
Contributor:
Francesca Varrone
,
Emilia Caputo

Scientific investigations have shown the involvement of microRNAs (miRNAs) as a new key factor for cancer development and progression. Owing to their role in the regulation of gene expression and their stability (resistance to endogenous RNase activity) in body fluids, miRNAs have been extensively shown to be of particular interest for diagnosis, recurrence, identification, and treatment of cancer metastasis. 

Despite miRNAs being considered small conserved regulators with the limitation of target specificity, we outline the dual role of melanoma-associated miRNAs, as oncogenic and/or tumor suppressive factors, compared to other tumors. 

  • melanoma
  • oncomiRNAs
  • tumor suppressor miRNAs

1. Introduction

It has been widely demonstrated that miRNAs are able to modulate the expression of multiple targets, some of which play oncogenic or tumor-suppressive roles.

2. The Dual Role of miRNAs in Cancer

Evidence suggests that some miRNAs can also have opposite effects in different tumoral contexts, as listed in Table 1.

Table 1. The most representative miRNAs with an opposite role in melanoma and other tumors.

miRNA

References

miR-9

[1][2]

miR-21

[3][4]

MiR-30b

[5][6][7]

MiR-30d

[5][6][7][8]

miR-125b

[9][10]

miR-155

[11][12][13]

miR-146a

[14][15]

miR-205-5p

[16][17][18][19][20]

miR-211

[21]

miR-224 5p

 [22][23][24]

miR-452

[25][23][26]

miR-542-3p

[27][28][29]

Notably, the dual role of miRs and the melanoma system has been established, as summarized in Table 1. For instance, among the tumor suppressors, Skouti et al. showed miR-205-5p gradually decreased during melanomagenesis in mice and was able to reduce cell and proliferation, and delay tumor initiation [16].

Several studies have focused on miR-205-5p and its dual role in cancer. It has been reported as oncomiR in lung and nasopharyngeal cancers by targeting PTEN [17][18][30]. Furthermore, a tumor suppressor role has also been described in prostate [19], breast [20], melanoma [31], glioblastoma [32], and colon cancers [33] by targeting c-MYC [34], PKCε [19], and VEGF-A [32]. Further, miR-9 has been found to be downregulated in metastatic melanomas compared to primary tumors. It has been shown to be able to downregulate SNAIL1 and consequently promote CDH1 expression, inhibiting melanoma cells’ ability to invade [35] while miR-9 has been described either as an oncomiR or tumor suppressor in a variety of other cancers [2].

MiR-21 negatively regulates MKK3 and acts as a tumor suppressor in melanoma by inhibiting cell growth and metastasis [3]. Instead, miR-21 inhibits tumor apoptosis and promotes proliferation and metastasis by downregulating p53 expression in uveal melanoma cell lines [4]. miR-125b represents another example of a miRNA able to act as either an oncomiR or a tumor suppressor, depending on the context. It acts as an oncomiR in the vast majority of hematologic malignancies but as a tumor suppressor in many solid tumors. This apparent paradox can be explained by considering the fact that a single miR-125b targets antiapoptotic factors (MCL1, BCL2L2, and BCL2), proapoptotic factors (TP53, BAK1, BMF, BBC3, and MAPK14), proproliferative factors (JUN, STAT3, E2F3, IL6R, and ERBB2/3), metastasis promoters (MMP13, LIN28B, and ARID3B), and metastasis inhibitors.

MiR-125b has been found to be upregulated in some tumor types, e.g., colon cancer and hematopoietic tumors, where it displays an oncogenic potential, by inducing cell growth and proliferation and blocking apoptosis. In contrast, it acts in other tumor entities, e.g., melanoma, as a tumor suppressor by targeting c-Jun [9][10].

Indeed, miR-155 shows a dual role in various types of cancer cells, such as melanoma. Although miR-155 has been described as an oncogene in various type of cancers, Levati and colleagues demonstrated that miR-155 is able to inhibit the proliferation of melanoma cell lines by targeting the oncongene SKI [11]. Similarly, Li and colleagues and Qin and colleagues demonstrated that miR-155 exerts a tumor-suppressive effect in gastric cancer and ovarian cancer-initiating cells by targeting SMAD2 and CLDN1, respectively [13]. Another excellent example of the opposite roles is provided by miR-30d and miR-30b-5p, which are associated with progression from primary to metastatic melanoma [36].

MiR-30d acts as a tumor suppressor in prostate cancer cell proliferation and migration by targeting NT5E and is regulated by the Akt/FOXO pathway in renal cell carcinoma [7][8]. MiR-30b-5p acts as a tumor suppressor microRNA in esophageal squamous cell carcinoma [5]. MiR-30b suppresses tumor migration and invasion by targeting EIF5A2 expression in gastric cancer cells [6].

Furthermore, miR-146a has been shown to play a dual role in malignancy. MiR-146a has been identified as being able to promote the tumor growth of malignant melanoma and, at the same time, to impair tumor cell dissemination. High levels of miR-146a expression during melanoma progression triggers tumor growth through inhibition of lunatic fringe (LFNG) and NUMB and activation of the NOTCH/PTEN/AKT pathway. In contrast its downregulation in circulating tumor cells (CTCs) suppresses tumor dissemination through modulation of the expression of ITGAV and ROCK1 [14][15].

It has been shown that miR-211 exhibited a dual role in melanoma progression, promoting cell proliferation while inhibiting metastatic spread in a xenograft mice model [21].

High expression levels of miR-224-5p have been detected in a large variety of tumors, such as glioma, colorectal cancer, and renal carcinoma, and is downregulated in uveal melanoma. Notably, Li et al. showed that miR-224-5p is involved in the proliferation, invasion, and migration of uveal melanoma (UM) cells via regulation of the expression of PIK3R3 and AKT3 [22]. Results from Gan et al. highlighted the correlation of the downregulated expression of miR-224-5p with the clinical progression and prognosis of prostate cancer [24]. Knoll et al. showed that the miR-224/miR-452 cluster is significantly increased in advanced melanoma and that ectopic expression of miR-224/miR-452 induces EMT and cytoskeletal rearrangements, and enhances migration/invasion. Conversely, miR-224/miR-452 depletion in metastatic cells induces the reversal of EMT, inhibition of motility, loss of the invasive phenotype, and an absence of lung metastases in mice.

It has been shown that miR-224/miR-452 targets the metastasis suppressor TXNIP and induces feedback inhibition of E2F1. MiR-224/452-mediated downregulation of TXNIP is essential for E2F1-induced EMT and invasion [37]. Also, the tumor-suppressive role of miR-452 has been reported in gliomas, targeting stemness regulators, such as BMI-1 [34].

The Rang group’s results collectively indicated that miR-542-3p acts as a metastasis suppressor in melanoma [27] and as a tumor suppressor in ovarian cancer by directly targeting CDK14 ) and promoting the proliferation of osteosarcoma cells in vitro [38][39][40]. Furthermore, Haflidadóttir et al. reported miR148’s dual/opposite role in MITF regulation [41].

This set of observations highlights the polyvalence of miRNAs as an oncogenic or tumor suppressor, even within a single cancer type.

This entry is adapted from the peer-reviewed paper 10.3390/ijms21030878

References

  1. Altaf A Dar; Shahana Majid; Claudia Rittsteuer; David De Semir; Vladimir Bezrookove; Schuyler Tong; Mehdi Nosrati; Richard Sagebiel; James R. Miller; Mohammed Kashani-Sabet; et al. The role of miR-18b in MDM2-p53 pathway signaling and melanoma progression.. JNCI: Journal of the National Cancer Institute 2013, 105, 433-42, 10.1093/jnci/djt003.
  2. S. J. Seashols-Williams; W. Budd; G. C. Clark; Q. Wu; R. Daniel; E. Dragoescu; Z. E. Zehner; miR-9 Acts as an OncomiR in Prostate Cancer through Multiple Pathways That Drive Tumour Progression and Metastasis. PLOS ONE 2016, 11, e0159601, 10.1371/journal.pone.0159601.
  3. Meng Zhou; Xiaoqian Yu; Zhenhai Jing; Wei Wu; Chenglong Lu; Overexpression of microRNA‑21 inhibits the growth and metastasis of melanoma cells by targeting MKK3.. Molecular Medicine Reports 2019, 20, 1797-1807, 10.3892/mmr.2019.10408.
  4. Hui Wang; Zheqiong Tan; Hui Hu; Hongzhou Liu; Tangwei Wu; Chao Zheng; Xiuling Wang; Zhenzhao Luo; Jing Wang; Shuiyi Liu; et al. microRNA-21 promotes breast cancer proliferation and metastasis by targeting LZTFL1.. BMC Cancer 2019, 19, 738-13, 10.1186/s12885-019-5951-3.
  5. Jianfeng Xu; Haiyan Lv; Bo Zhang; Feng Xu; Hongyu Zhu; Baofu Chen; Chengchu Zhu; Jianfei Shen; miR-30b-5p acts as a tumor suppressor microRNA in esophageal squamous cell carcinoma.. Journal of Thoracic Disease 2019, 11, 3015-3029, 10.21037/jtd.2019.07.50.
  6. Shu-Bo Tian; Jian-Chun Yu; Yu-Qin Liu; Wei-Ming Kang; Zhi-Qiang Ma; Xin Ye; Chao Yan; MiR-30b suppresses tumor migration and invasion by targeting EIF5A2 in gastric cancer. World Journal of Gastroenterology 2015, 21, 9337-9347, 10.3748/wjg.v21.i31.9337.
  7. Yongbo Song; Chao Song; Sixing Yang; Tumor-Suppressive Function of miR-30d-5p in Prostate Cancer Cell Proliferation and Migration by Targeting NT5E.. Cancer Biotherapy and Radiopharmaceuticals 2018, 33, 203-211, 10.1089/cbr.2018.2457.
  8. Chenglin Wu; Bo Jin; Liting Chen; Dexiang Zhuo; Zheng Zhang; Kan Gong; Zebin Mao; MiR-30d induces apoptosis and is regulated by the Akt/FOXO pathway in renal cell carcinoma. Cellular Signalling 2013, 25, 1212-1221, 10.1016/j.cellsig.2013.01.028.
  9. M Kappelmann; S Kuphal; G Meister; L Vardimon; A-K Bosserhoff; MicroRNA miR-125b controls melanoma progression by direct regulation of c-Jun protein expression. Oncogene 2012, 32, 2984-2991, 10.1038/onc.2012.307.
  10. Julia Banzhaf-Strathmann; Dieter Edbauer; Good guy or bad guy: the opposing roles of microRNA 125b in cancer. Cell Communication and Signaling 2014, 12, 30-30, 10.1186/1478-811X-12-30.
  11. Lauretta Levati; Elena Pagani; Sveva Romani; Daniele Castiglia; Eugenia Piccinni; Claudia Covaciu; Patrizia Caporaso; Sergio Bondanza; Francesca R. Antonetti; Enzo Bonmassar; et al. MicroRNA-155 targets the SKI gene in human melanoma cell lines. Pigment Cell & Melanoma Research 2011, 24, 538-550, 10.1111/j.1755-148x.2011.00857.x.
  12. Yi Li; Lugen Zuo; Weiming Zhu; Jianfeng Gong; Wei Zhang; Zhen Guo; Lili Gu; Ning Li; Jieshou Li; Telmisartan attenuates the inflamed mesenteric adipose tissue in spontaneous colitis by mechanisms involving regulation of neurotensin/microRNA-155 pathway. Biochemical Pharmacology 2015, 93, 461-469, 10.1016/j.bcp.2014.12.020.
  13. Wenxing Qin; Qiusheng Ren; Te Liu; Yongyi Huang; Jiejun Wang; MicroRNA-155 is a novel suppressor of ovarian cancer-initiating cells that targets CLDN1. FEBS Letters 2013, 587, 1434-1439, 10.1016/j.febslet.2013.03.023.
  14. Monica Raimo; Francesca Orso; Elena Grassi; Daniela Cimino; Elisa Penna; Cristiano De Pittà; Michael B. Stadler; Luca Primo; Enzo Calautti; Pietro Quaglino; et al. miR-146a Exerts Differential Effects on Melanoma Growth and Metastatization. Molecular Cancer Research 2016, 14, 548-562, 10.1158/1541-7786.mcr-15-0425-t.
  15. Matteo Forloni; Shaillay Kumar Dogra; Yuying Dong; Darryl Conte; Jianhong Ou; Lihua Julie Zhu; April Deng; Meera Mahalingam; Michael R Green; Narendra Wajapeyee; et al. miR-146a promotes the initiation and progression of melanoma by activating Notch signaling. eLife 2014, 3, e01460, 10.7554/eLife.01460.
  16. Elena Skourti; Stella Logotheti; Christos K. Kontos; Athanasia Pavlopoulou; Paraskevi T. Dimoragka; Ioannis P. Trougakos; Vassilis Gorgoulis; Andreas Scorilas; Ioannis Michalopoulos; Vassilis Zoumpourlis; et al. Progression of mouse skin carcinogenesis is associated with the orchestrated deregulation of mir-200 family members, mir-205 and their common targets. Molecular Carcinogenesis 2015, 55, 1229-1242, 10.1002/mc.22365.
  17. Junchao Cai; Lishan Fang; Yongbo Huang; Rong Li; Jie Yuan; Y. Yang; Xun Zhu; Baixue Chen; Jueheng Wu; Mengfeng Li; et al. miR-205 Targets PTEN and PHLPP2 to Augment AKT Signaling and Drive Malignant Phenotypes in Non-Small Cell Lung Cancer. Cancer Research 2013, 73, 5402-5415, 10.1158/0008-5472.can-13-0297.
  18. Changju Qu; Zhihui Liang; Jialing Huang; Ruiying Zhao; Chunhui Su; Sumei Wang; Xudan Wang; Rong Zhang; Mong-Hong Lee; Huiling Yang; et al. MiR-205 determines the radioresistance of human nasopharyngeal carcinoma by directly targeting PTEN. Cell Cycle 2012, 11, 785-796, 10.4161/cc.11.4.19228.
  19. Gandellini, P.; Folini, M.; Longoni, N.; Pennati, M.; Binda, M.; Colecchia, M.; Salvioni, R.; Supino, R.; Moretti, R.; Limonta, P.; et al. miR-205 Exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. . Cancer Res. 2009, 69, 2287–2295., .
  20. Hailong Wu; Shoumin Zhu; Yin-Yuan Mo; Suppression of cell growth and invasion by miR-205 in breast cancer. Cell Research 2009, 19, 439-48, 10.1038/cr.2009.18.
  21. Golan, T.; Parikh, R.; Jacob, E.; Vaknine, H.; Zemser-Werner, V.; Hershkovitz, D.; Malcov, H.; Leibou, S.; Reichman, H.; Sheinboim, D.; et al. Adipocytes sensitize melanoma cells to environmental TGF-beta cues by repressing the expression of miR-211. . Sci. Signal. 2019, 12, 1, .
  22. Jianchang Li; Xiuming Liu; Chaopeng Li; Wenqi Wang; miR-224-5p inhibits proliferation, migration, and invasion by targeting PIK3R3/AKT3 in uveal melanoma.. Journal of Cellular Biochemistry 2019, 120, 12412-12421, 10.1002/jcb.28507.
  23. Susanne Knoll; Katharina Fürst; Bhavani Kowtharapu; Ulf Schmitz; Stephan Marquardt; Olaf Wolkenhauer; Hubert Martin; Brigitte M Pützer; E2F1 induces miR‐224/452 expression to drive EMT through TXNIP downregulation. EMBO reports 2014, 15, 1315-1329, 10.15252/embr.201439392.
  24. Bin‑Liang Gan; Li‑Jie Zhang; Li Gao; Fu‑Chao Ma; Rong‑Quan He; Gang Chen; Jie Ma; Jin‑Cai Zhong; Xiao‑Hua Hu; Downregulation of miR‑224‑5p in prostate cancer and its relevant molecular mechanism via TCGA, GEO database and in silico analyses.. Oncology Reports 2018, 40, 3171-3188, 10.3892/or.2018.6766.
  25. S. Noguchi; M. Kumazaki; T. Mori; K. Baba; M. Okuda; T. Mizuno; Y. Akao; Analysis of microRNA-203 function in CREB/MITF/RAB27a pathway: comparison between canine and human melanoma cells. Veterinary and Comparative Oncology 2014, 14, 384-394, 10.1111/vco.12118.
  26. Li, T.; Jian, X.; He, H.; Lai, Q.; Li, X.; Deng, D.; Liu, T.; Zhu, J.; Jiao, H.; Ye, Y.; et al. MiR-452 promotes an aggressive colorectal cancer phenotype by regulating a Wnt/beta-catenin positive feedback loop. . J. Exp. Clin. Cancer Res. 2018, 37, 238, .
  27. Zhen Rang; Ge Yang; You-Wei Wang; Fan Cui; miR-542-3p suppresses invasion and metastasis by targeting the proto-oncogene serine/threonine protein kinase, PIM1, in melanoma. Biochemical and Biophysical Research Communications 2016, 474, 315-320, 10.1016/j.bbrc.2016.04.093.
  28. Yinsheng Wu; Jiongming You; Feng Li; Feng Wang; Yong Wang; MicroRNA-542-3p suppresses tumor cell proliferation via targeting Smad2 inhuman osteosarcoma. Oncology Letters 2018, 15, 6895-6902, 10.3892/ol.2018.8238.
  29. Dong-Dong Cheng; Tao Yu; Tu Hu; Ming Yao; Cun-Yi Fan; Qing-Cheng Yang; MiR-542-5p is a negative prognostic factor and promotes osteosarcoma tumorigenesis by targeting HUWE1. Oncotarget 2015, 6, 42761-42772, 10.18632/oncotarget.6199.
  30. Jinghui Bai; Xiangyu Zhu; Jianqi Ma; Wanting Wang; miR-205 regulates A549 cells proliferation by targeting PTEN. International journal of clinical and experimental pathology 2015, 8, 1175-1183, .
  31. Y Xu; T Brenn; E R S Brown; V Doherty; D W Melton; Differential expression of microRNAs during melanoma progression: miR-200c, miR-205 and miR-211 are downregulated in melanoma and act as tumour suppressors. British Journal of Cancer 2012, 106, 553-561, 10.1038/bjc.2011.568.
  32. Xiao Yue; Peiguo Wang; Jun Xu; Yufang Zhu; Guan Sun; Qi Pang; Rongjie Tao; MicroRNA-205 functions as a tumor suppressor in human glioblastoma cells by targeting VEGF-A. Oncology Reports 2011, 27, 1200-1206, 10.3892/or.2011.1588.
  33. Li, P.; Xue, W.J.; Feng, Y.; Mao, Q.S.; MicroRNA-205 functions as a tumor suppressor in colorectal cancer by targeting cAMP responsive element binding protein 1 (CREB1). . Am. J. Transl. Res. 2015, 7, 2053–2059., .
  34. Mohit Sachdeva; Shoumin Zhu; Fangting Wu; Hailong Wu; Vijay Walia; Sumit Kumar; Randolph Elble; Kounosuke Watabe; Yin-Yuan Mo; p53 represses c-Myc through induction of the tumor suppressor miR-145. Proceedings of the National Academy of Sciences 2009, 106, 3207-3212, 10.1073/pnas.0808042106.
  35. Antoni Ribas; Donald Lawrence; Victoria Atkinson; Sachin Agarwal; Wilson H. Miller; Matteo S. Carlino; Rosalie Fisher; Georgina V. Long; F. Stephen Hodi; Jennifer Tsoi; et al. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nature Medicine 2019, 25, 936-940, 10.1038/s41591-019-0476-5.
  36. Avital Gaziel-Sovran; Miguel F. Segura; Raffaella Di Micco; Mary K. Collins; Uglas Hanniford; Eleazar Vega-Saenz De Miera; John F. Rakus; John F. Dankert; Shulian Shang; Robert S. Kerbel; et al. miR-30b/30d regulation of GalNAc transferases enhances invasion and immunosuppression during metastasis.. Cancer Cell 2011, 20, 104-18, 10.1016/j.ccr.2011.05.027.
  37. Elisa Penna; Francesca Orso; Daniela Cimino; Enrico Tenaglia; Antonio Lembo; Elena Quaglino; Laura Poliseno; Adele Haimovic; Simona Osella-Abate; Cristiano De Pittà; et al. microRNA-214 contributes to melanoma tumour progression through suppression of TFAP2C. The EMBO Journal 2011, 30, 1990-2007, 10.1038/emboj.2011.102.
  38. Yusuke Goto; Satoko Kojima; Akira Kurozumi; Mayuko Kato; Atsushi Okato; Ryosuke Matsushita; Tomohiko Ichikawa; Naohiko Seki; Regulation of E3 ubiquitin ligase-1 (WWP1) by microRNA-452 inhibits cancer cell migration and invasion in prostate cancer. British Journal of Cancer 2016, 114, 1135-1144, 10.1038/bjc.2016.95.
  39. Jingwei Li; Wei Shao; Huian Feng; MiR-542-3p, a microRNA targeting CDK14, suppresses cell proliferation, invasiveness, and tumorigenesis of epithelial ovarian cancer. Biomedicine & Pharmacotherapy 2019, 110, 850-856, 10.1016/j.biopha.2018.11.104.
  40. Ng Cheng; Xubin Qiu; Ming Zhuang; Chenlei Zhu; Hongjun Zou; Zhiwei Liu; MicroRNAs with prognostic significance in osteosarcoma: a systemic review and meta-analysis. Oncotarget 2017, 8, 81062-81074, 10.18632/oncotarget.19009.
  41. Benedikta S. Haflidadóttir; Kristín Bergsteinsdóttir; Christian Praetorius; Eiríkur Steingrímsson; miR-148 Regulates Mitf in Melanoma Cells. PLOS ONE 2010, 5, e11574, 10.1371/journal.pone.0011574.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback