CoChat
Sign Up
Cited by 72Multiple Myeloma Research and TreatmentsMicroRNA in disease regulationChronic Lymphocytic Leukemia Research

Low serum mi R‐19a expression as a novel poor prognostic indicator in multiple myeloma

Open access
Hao, Mu, Zang, Meirong, Wendlandt, Erik, Xu, Yan, An, Gang, Gong, Dasen, Li, Fei, Qi, Fang +4 more·2015·International Journal of Cancer
DOI 10.1002/ijc.29199PMC PMC4382914
Open this paper in CoChat — free accountOpen PDF

Abstract

Multiple myeloma (MM) is the second most common hematologic malignancy characterized by the clonal expansion of plasma cells. Despite continuing advances, novel biomarkers are needed for diagnosis and prognosis of MM. In our study, we characterized the diagnostic and prognostic potential of circulating microRNAs (miRNAs) in MM. Serum miRNA levels were analyzed in 108 newly diagnosed symptomatic MM patients and 56 healthy donors (HDs). Our analysis identified 95 dysregulated miRNAs in newly diagnosed MM patients. Of the 95 dysregulated miRNAs, dysregulation of miR‐19a, miR‐92a, miR‐214‐3p, miR‐135b‐5p, miR‐4254, miR‐3658 and miR‐33b was confirmed by quantitative reverse transcription PCR (RT‐qPCR). Receiver operating characteristic analysis revealed that a combination of miR‐19a and miR‐4254 can distinguish MM from HD with a sensitivity of 91.7% and specificity of 90.5%. Decreased expression of miR‐19a was positively correlated with international staging system advancement, del(13q14) and 1q21 amplification. Furthermore, downregulation of miR‐19a resulted in significantly decreased progression‐free survival (PFS) and overall survival (OS). Our analysis indicated that the poor prognostic correlation of miR‐19a expression was independent of genetic abnormalities in MM. Multivariate analysis revealed that miR‐19a was a significant predictor of shortened PFS and OS. Interestingly, although miR‐19a levels portend a poor prognosis, patients with low miR‐19a levels had an improved response to bortezomib compared to those with high miR‐19a profile. Patients with downregulated miR‐19a experienced a significantly extended survival upon bortezomib‐based therapy. These data demonstrate that the expression patterns of serum microRNAs are altered in MM, and miR‐19a levels are a valuable prognostic marker to identify high‐risk MM.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/ijc.29199

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • miR-33b-5p is predominantly upregulated in multiple myeloma after proteasome inhibitor treatment.

    “It drew our attention that miR-33b-5p was predominantly upregulated in multiple myeloma post treatment with proteasome inhibitor (15, 16).”

    From miR-33b-3p Acts as a Tumor Suppressor by Targeting DOCK4 in Prostate Cancer (2021) · cites this paper as [15]

    The Results (Validation of candidate miRNAs using RT-qPCR; page unavailable) report increased serum miR-33b in newly diagnosed multiple myeloma patients compared with healthy donors. They do not identify the measured form as miR-33b-5p or show that it was upregulated after proteasome inhibitor treatment. The paper’s bortezomib-treatment analysis concerns miR-19a, not miR-33b. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

No references could be resolved yet.

Research works printed but not linked: 58

  1. [1]Raab MS Podar K Breitkreutz I Richardson PG Anderson KC Multiple myeloma Lancet 2009 374 324 339 19541364
  2. [2]Anderson KC Shaughnessy JD Jr Barlogie B Harousseau JL Roodman GD Multiple myeloma Hematology Am Soc Hematol Educ Program 2002 214 240 12446425
  3. [3]Vicente-Duenas C Romero-Camarero I Garcia-Criado FJ Cobaleda C Sanchez-Garcia I The cellular architecture of multiple myeloma Cell cycle 2012 11 3715 3717 22983005 PMC3495807
  4. [4]Yang Y Shi J Tolomelli G Xu H Xia J Wang H Zhou W Zhou Y Das S Gu Z Levasseur D Zhan F RARalpha2 expression confers myeloma stem cell features Blood 2013 122 1437 1447 23847194 PMC3750340
  5. [5]Zhou W Yang Y Xia J Wang H Salama ME Xiong W Xu H Shetty S Chen T Zeng Z Shi L Zangari M NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers Cancer cell 2013 23 48 62 23328480 PMC3954609
  6. [6]Zhou W Yang Y Gu Z Wang H Xia J Wu X Zhan X Levasseur D Zhou Y Janz S Tricot G Shi J ALDH1 activity identifies tumor-initiating cells and links to chromosomal instability signatures in multiple myeloma Leukemia 2014 28 1155 1158 24365790 PMC4018236
  7. [7]Jones CI Zabolotskaya MV King AJ Stewart HJ Horne GA Chevassut TJ Newbury SF Identification of circulating microRNAs as diagnostic biomarkers for use in multiple myeloma British journal of cancer 2012 107 1987 1996 23169280 PMC3516695
  8. [8]Yyusnita Norsiah Zakiah I Chang KM Purushotaman VS Zubaidah Z Jamal R MicroRNA (miRNA) expression profiling of peripheral blood samples in multiple myeloma patients using microarray The Malaysian journal of pathology 2012 34 133 143 23424776
  9. [9]Sevcikova S Kubiczkova L Sedlarikova L Slaby O Hajek R Serum miR-29a as a marker of multiple myeloma Leukemia & lymphoma 2013 54 189 191 22712836
  10. [10]Kubiczkova L Kryukov F Slaby O Dementyeva E Jarkovsky J Nekvindova J Radova L Greslikova H Kuglik P Vetesnikova E Pour L Adam Z Circulating serum microRNAs as novel diagnostic and prognostic biomarkers for multiple myeloma and monoclonal gammopathy of undetermined significance Haematologica 2014 99 511 518 24241494 PMC3943315
  11. [11]Baek D Villen J Shin C Camargo FD Gygi SP Bartel DP The impact of microRNAs on protein output Nature 2008 455 64 71 18668037 PMC2745094
  12. [12]Grosshans H Filipowicz W Molecular biology: the expanding world of small RNAs Nature 2008 451 414 416 18216846
  13. [13]Lewis BP Burge CB Bartel DP Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets Cell 2005 120 15 20 15652477
  14. [14]Krek A Grun D Poy MN Wolf R Rosenberg L Epstein EJ MacMenamin P da Piedade I Gunsalus KC Stoffel M Rajewsky N Combinatorial microRNA target predictions Nature genetics 2005 37 495 500 15806104
  15. [15]Lim LP Lau NC Garrett-Engele P Grimson A Schelter JM Castle J Bartel DP Linsley PS Johnson JM Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs Nature 2005 433 769 773 15685193
  16. [16]Tian Z Zhao JJ Tai YT Amin SB Hu Y Berger AJ Richardson P Chauhan D Anderson KC Investigational agent MLN9708/2238 targets tumor-suppressor miR33b in MM cells Blood 2012 120 3958 3967 22983447 PMC3496955
  17. [17]Wu P Agnelli L Walker BA Todoerti K Lionetti M Johnson DC Kaiser M Mirabella F Wardell C Gregory WM Davies FE Brewer D Improved risk stratification in myeloma using a microRNA-based classifier British journal of haematology 2013 162 348 359 23718138
  18. [18]Dimopoulos K Gimsing P Gronbaek K Aberrant microRNA expression in multiple myeloma European journal of haematology 2013 91 95 105 23586898
  19. [19]Lionetti M Biasiolo M Agnelli L Todoerti K Mosca L Fabris S Sales G Deliliers GL Bicciato S Lombardi L Bortoluzzi S Neri A Identification of microRNA expression patterns and definition of a microRNA/mRNA regulatory network in distinct molecular groups of multiple myeloma Blood 2009 114 e20 e6 19846888
  20. [20]Zhou Y Chen L Barlogie B Stephens O Wu X Williams DR Cartron MA van Rhee F Nair B Waheed S Pineda-Roman M Alsayed Y High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2 Proceedings of the National Academy of Sciences of the United States of America 2010 107 7904 7909 20385818 PMC2867889
  21. [21]Mitchell PS Parkin RK Kroh EM Fritz BR Wyman SK Pogosova-Agadjanyan EL Peterson A Noteboom J O'Briant KC Allen A Lin DW Urban N Circulating microRNAs as stable blood-based markers for cancer detection Proceedings of the National Academy of Sciences of the United States of America 2008 105 10513 10518 18663219 PMC2492472
  22. [22]Schwarzenbach H Hoon DS Pantel K Cell-free nucleic acids as biomarkers in cancer patients. Nature reviews Cancer 2011 11 426 437 21562580
  23. [23]An G Xu Y Shi L Shizhen Z Deng S Xie Z Sui W Zhan F Qiu L Chromosome 1q21 gains confer inferior outcomes in multiple myeloma treated with bortezomib but copy number variation and percentage of plasma cells involved have no additional prognostic value Haematologica 2014 99 353 359 24213147 PMC3912967
  24. [24]Zhu W Yang L Shan H Zhang Y Zhou R Su Z Du Z MicroRNA expression analysis: clinical advantage of propranolol reveals key microRNAs in myocardial infarction PloS one 2011 6 e14736 21386882 PMC3046111
  25. [25]Li S Zhu J Zhang W Chen Y Zhang K Popescu LM Ma X Lau WB Rong R Yu X Wang B Li Y Signature microRNA expression profile of essential hypertension and its novel link to human cytomegalovirus infection Circulation 2011 124 175 184 21690488
  26. [26]Liu Y Lai L Chen Q Song Y Xu S Ma F Wang X Wang J Yu H Cao X Wang Q MicroRNA-494 is required for the accumulation and functions of tumor-expanded myeloid-derived suppressor cells via targeting of PTEN J Immunol 2012 188 5500 5510 22544933
  27. [27]Tie J Pan Y Zhao L Wu K Liu J Sun S Guo X Wang B Gang Y Zhang Y Li Q Qiao T MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor PLoS genetics 2010 6 e1000879 20300657 PMC2837402
  28. [28]Yan HL Xue G Mei Q Wang YZ Ding FX Liu MF Lu MH Tang Y Yu HY Sun SH Repression of the miR-17–92 cluster by p53 has an important function in hypoxia-induced apoptosis The EMBO journal 2009 28 2719 2732 19696742 PMC2750010
  29. [29]Lin ZY Huang YQ Zhang YQ Han ZD He HC Ling XH Fu X Dai QS Cai C Chen JH Liang YX Jiang FN MicroRNA-224 inhibits progression of human prostate cancer by downregulating TRIB1. International journal of cancer Journal international du cancer 2013 24382668
  30. [30]Eguchi T Watanabe K Hara ES Ono M Kuboki T Calderwood SK OstemiR: a novel panel of microRNA biomarkers in osteoblastic and osteocytic differentiation from mesencymal stem cells PloS one 2013 8 e58796 23533592 PMC3606401
  31. [31]Anderson KC Kyle RA Rajkumar SV Stewart AK Weber D Richardson P Clinically relevant end points and new drug approvals for myeloma Leukemia 2008 22 231 239 17972944
  32. [32]Resnick KE Alder H Hagan JP Richardson DL Croce CM Cohn DE The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform Gynecologic oncology 2009 112 55 59 18954897
  33. [33]Chen X Ba Y Ma L Cai X Yin Y Wang K Guo J Zhang Y Chen J Guo X Li Q Li X Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases Cell research 2008 18 997 1006 18766170
  34. [34]Gilad S Meiri E Yogev Y Benjamin S Lebanony D Yerushalmi N Benjamin H Kushnir M Cholakh H Melamed N Bentwich Z Hod M Serum microRNAs are promising novel biomarkers PloS one 2008 3 e3148 18773077 PMC2519789
  35. [35]Taylor DD Gercel-Taylor C MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer Gynecologic oncology 2008 110 13 21 18589210
  36. [36]Tsujiura M Ichikawa D Komatsu S Shiozaki A Takeshita H Kosuga T Konishi H Morimura R Deguchi K Fujiwara H Okamoto K Otsuji E Circulating microRNAs in plasma of patients with gastric cancers British journal of cancer 2010 102 1174 1179 20234369 PMC2853097
  37. [37]Garzon R Volinia S Liu CG Fernandez-Cymering C Palumbo T Pichiorri F Fabbri M Coombes K Alder H Nakamura T Flomenberg N Marcucci G MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia Blood 2008 111 3183 3189 18187662 PMC2265455
  38. [38]Zen K Zhang CY Circulating microRNAs: a novel class of biomarkers to diagnose and monitor human cancers Medicinal research reviews 2012 32 326 348 22383180
  39. [39]Palumbo A Anderson K Multiple myeloma The New England journal of medicine 2011 364 1046 1060 21410373
  40. [40]Fonseca R Bergsagel PL Drach J Shaughnessy J Gutierrez N Stewart AK Morgan G Van Ness B Chesi M Minvielle S Neri A Barlogie B International Myeloma Working Group molecular classification of multiple myeloma: spotlight review Leukemia 2009 23 2210 2221 19798094 PMC2964268
  41. [41]Kyle RA Durie BG Rajkumar SV Landgren O Blade J Merlini G Kroger N Einsele H Vesole DH Dimopoulos M San Miguel J Avet-Loiseau H Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management Leukemia 2010 24 1121 1127 20410922 PMC7020664
  42. [42]Munshi NC Anderson KC Bergsagel PL Shaughnessy J Palumbo A Durie B Fonseca R Stewart AK Harousseau JL Dimopoulos M Jagannath S Hajek R Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2 Blood 2011 117 4696 4700 21292777 PMC3293763
  43. [43]Yoshizawa S Ohyashiki JH Ohyashiki M Umezu T Suzuki K Inagaki A Iida S Ohyashiki K Downregulated plasma miR-92a levels have clinical impact on multiple myeloma and related disorders Blood cancer journal 2012 2 e53 22829237 PMC3270255
  44. [44]Halimi M Parsian H Asghari SM Sariri R Moslemi D Yeganeh F Zabihi E Clinical translation of human microRNA 21 as a potential biomarker for exposure to ionizing radiation Translational research: the journal of laboratory and clinical medicine 2014 24518062
  45. [45]Koberle V Kronenberger B Pleli T Trojan J Imelmann E Peveling-Oberhag J Welker MW Elhendawy M Zeuzem S Piiper A Waidmann O Serum microRNA-1 and microRNA-122 are prognostic markers in patients with hepatocellular carcinoma Eur J Cancer 2013 49 3442 3449 23810247
  46. [46]Hao M Zhang L An G Meng H Han Y Xie Z Xu Y Li C Yu Z Chang H Qiu L Bone marrow stromal cells protect myeloma cells from bortezomib induced apoptosis by suppressing microRNA-15a expression Leukemia & lymphoma 2011 52 1787 1794 21534877
  47. [47]Hao M Zhang L An G Sui W Yu Z Zou D Xu Y Chang H Qiu L Suppressing miRNA-15a/-16 expression by interleukin-6 enhances drug-resistance in myeloma cells Journal of hematology & oncology 2011 4 37 21936961 PMC3189173
  48. [48]Rocci A Hofmeister CC Geyer S Stiff A Gambella M Cascione L Guan J Benson DM Efebera YA Talabere T Dirisala V Smith EM Circulating miRNA markers show promise as new prognosticators for multiple myeloma Leukemia 2014 PMC4155011 24813918
  49. [49]Bartel DP MicroRNAs: genomics, biogenesis, mechanism, and function Cell 2004 116 281 297 14744438
  50. [50]Roth C Kasimir-Bauer S Pantel K Schwarzenbach H Screening for circulating nucleic acids and caspase activity in the peripheral blood as potential diagnostic tools in lung cancer Molecular oncology 2011 5 281 291 21398193 PMC5528292
  51. [51]Ouchida M Kanzaki H Ito S Hanafusa H Jitsumori Y Tamaru S Shimizu K Novel direct targets of miR-19a identified in breast cancer cells by a quantitative proteomic approach PloS one 2012 7 e44095 22952885 PMC3431339
  52. [52]Lin TL Wang QH Brown P Peacock C Merchant AA Brennan S Jones E McGovern K Watkins DN Sakamoto KM Matsui W Self-renewal of acute lymphocytic leukemia cells is limited by the Hedgehog pathway inhibitors cyclopamine and IPI-926 PloS one 2010 5 e15262 21203400 PMC3011010
  53. [53]Yu L Simonson OE Mohamed AJ Smith CI NF-kappaB regulates the transcription of protein tyrosine kinase Tec FEBS J 2009 276 6714 6724 19843184
  54. [54]Ye H Liu X Lv M Wu Y Kuang S Gong J Yuan P Zhong Z Li Q Jia H Sun J Chen Z MicroRNA and transcription factor co-regulatory network analysis reveals miR-19 inhibits CYLD in T-cell acute lymphoblastic leukemia Nucleic acids research 2012 40 5201 5214 22362744 PMC3384304
  55. [55]Li ZW Chen H Campbell RA Bonavida B Berenson JR NF-kappaB in the pathogenesis and treatment of multiple myeloma Current opinion in hematology 2008 15 391 399 18536579
  56. [56]Grillari J Hackl M Grillari-Voglauer R miR-17–92 cluster: ups and downs in cancer and aging Biogerontology 2010 11 501 506 20437201 PMC2899009
  57. [57]Olive V Bennett MJ Walker JC Ma C Jiang I Cordon-Cardo C Li QJ Lowe SW Hannon GJ He L miR-19 is a key oncogenic component of mir-17–92 Genes & development 2009 23 2839 2849 20008935 PMC2800084
  58. [58]Wang F Li T Zhang B Li H Wu Q Yang L Nie Y Wu K Shi Y Fan D MicroRNA-19a/b regulates multidrug resistance in human gastric cancer cells by targeting PTEN Biochemical and biophysical research communications 2013 434 688 694 23603256

Cited by

Sorted by citations

Authors
Hao, M., Zang, M., Wendlandt, E., Xu, Y., An, G., Gong, D., Li, F., Qi, F., Zhang, Y., Yang, Y., Zhan, F., & Qiu, L.
Affiliations
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • University of Iowa (US)
  • Tianjin Medical University General Hospital (CN)
Corresponding author
Qiu, Lugui
ORCID
Venue
International Journal of Cancer
Publisher
Wiley
Published
2014-09-19
Volume
136
Issue
8
Pages
1835-1844
ISSN
  • 0020-7136 (ISSN-L)
  • 1097-0215
DOI
10.1002/ijc.29199
PMC
PMC4382914
OpenAlex
W2127008908
Cited by
72
References
0
Citations by year
2026: 1 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 4 · 2021: 8 · 2020: 11 · 2019: 6 · 2018: 6 · 2017: 11 · 2016: 6 · 2015: 6
FWCI
5.44
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • International Journal of Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Natural Science Foundation of China (81400174, 81172255, 81370632)
  • Tianjin Science and Technology Supporting Program (13JCQNJC12800)
  • Foundation of MOE of China (20111106120037)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
Keywords
multiple myeloma, miR-19a, serum microRNA, prognostic factors, diagnostic biomarkers, miR-135b-5p, miR-92a, miR-214-3p, miR-33b, progression-free survival, overall survival, del(13q14), 1q21 amplification, International Staging System
MeSH terms
Adult, Aged, Humans, Middle Aged, Multiple Myeloma, Prognosis, Biomarkers, Tumor, Down-Regulation, Gene Expression Regulation, Neoplastic, Disease-Free Survival, MicroRNAs, Serum, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review