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Cited by 26MicroRNA in disease regulationCancer-related molecular mechanisms researchLung Cancer Research Studies

The miR-23a/27a/24-2 cluster promotes postoperative progression of early-stage non-small cell lung cancer

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Fan, Xiaoqing, Tao, Shaolin, Li, Qing, Deng, Bo, Tan, Qun-You, Jin, Hua·2022·Molecular Therapy - Oncolytics
DOI 10.1016/j.omto.2021.12.014PMC PMC8760463
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Abstract

Even with optimal surgery, many early-stage non-small cell lung cancer (NSCLC) patients die of recurrence. Unfortunately, there are no precise predictors for postoperative recurrence in early-stage NSCLC, and the recurrence mechanism is still unclear. In this study, we found that simultaneous overexpression of all miRNAs in the miR-23a/27a/24-2 cluster was closely associated with postoperative recurrence, β-catenin upregulation and promoter methylation of p16 and CDH13 in early-stage NSCLC patients. In addition, in vitro and in vivo experiments show that overexpression or inhibition of all miRNAs in the miR-23a/27a/24-2 cluster significantly stimulated or inhibited NSCLC cell stemness, tumorigenicity and metastasis. Furthermore, we demonstrated that the miR-23a/27a/24-2 cluster miRNAs activated Wnt/β-catenin signaling by targeting their suppressors and stimulated promoter methylation-induced silencing of p16 and CDH13 by affecting DNA methylation-related genes expression. Our findings suggest that simultaneous high expression of all miRNAs in the miR-23a/27a/24-2 cluster represents a new biomarker for predicting postoperative recurrence in early-stage NSCLC. The miR-23a/27a/24-2 cluster miRNAs stimulate early-stage NSCLC progression through simultaneously stimulating Wnt/β-catenin signaling, and promoter methylation-induced tumor suppressor genes silencing. In addition, simultaneous inhibition of all miRNAs in the miR-23a/27a/24-2 cluster may be a useful strategy for treatment of early-stage NSCLC recurrence.

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  • Members of the miR-23a functional cluster are overexpressed in tumors and associated with an increased risk of postoperative recurrence in non-small cell lung cancer patients.

    “members of the miR-23a functional cluster are overexpressed in tumors and associated with an increased risk of postoperative recurrence in non-small cell lung cancer (NSCLC) patients.”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [91]

    The Results (Figure 1 and the accompanying text) report that simultaneous high expression of miR-23a, miR-27a, and miR-24-2 in primary tumors was associated with postoperative recurrence. The study concerns early-stage NSCLC, however, and its recurrence finding is for high expression of all three together, not necessarily each member independently across all NSCLC patients. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • miR-23a activates Wnt/β-catenin signaling by targeting its inhibitors and promotes silencing of tumor suppressor genes by affecting DNA methylation-related genes.

    “miR-23a activates the Wnt/β-catenin signaling pathway by targeting its inhibitors and promotes the silencing of tumor suppressor genes by affecting the expression of DNA methylation-related genes [91].”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [91]

    The Results and Discussion (page not provided) link the miR-23a/27a/24-2 cluster to suppression of Wnt/β-catenin inhibitors and to DNA methylation-related downregulation of tumor suppressor genes in NSCLC. The citing sentence attributes both effects to miR-23a alone, whereas the paper emphasizes the combined action of all three miRNAs; the Results state that only their combined overexpression produced the simultaneous changes in methylation-related genes and tumor suppressors. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Elevation of β-catenin and methylation of the p16 and CDH13 promoters have been linked to this over-expression.

    “The elevation of β-catenin and the methylation of the p16 and CDH13 promoters have also been linked to this over-expression.”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [91]

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  1. [1]Bray F. Ferlay J. Soerjomataram I. Siegel R.L. Torre L.A. Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J. Clin. 68 2018 394 424 30207593
  2. [2]Olak J. Ng A. Diagnosis and treatment of early-stage non-small cell lung cancer Oncologist 1 1996 201 209 10387989
  3. [3]Sonoda D. Matsuura Y. Ichinose J. Nakao M. Ninomiya H. Mun M. Ishikawa Y. Nakagawa K. Satoh Y. Okumura S. Ultra-late recurrence of non-small cell lung cancer over 10 years after curative resection Cancer Manag. Res. 11 2019 6765 6774 31410065 PMC6648654
  4. [4]Lee Y.C. Wu C.T. Chen C.S. Hsu H.H. Chang Y.L. The significance of E-cadherin and alpha-, beta-, and gamma-catenin expression in surgically treated non-small cell lung cancers of 3 cm or less in size J. Thorac. Cardiovasc. Surg. 123 2002 502 507 11882822
  5. [5]Stewart D.J. Wnt signaling pathway in non-small cell lung cancer J. Natl. Cancer Inst. 106 2014 djt356 24309006
  6. [6]Fang L. Cai J. Chen B. Wu S. Li R. Xu X. Yang Y. Guan H. Zhu X. Zhang L. Aberrantly expressed miR-582-3p maintains lung cancer stem cell-like traits by activating Wnt/beta-catenin signalling Nat. Commun. 6 2015 8640 26468775 PMC4667703
  7. [7]Toh T.B. Lim J.J. Chow E.K. Epigenetics in cancer stem cells Mol. Cancer 16 2017 29 28148257 PMC5286794
  8. [8]Brock M.V. Hooker C.M. Ota-Machida E. Han Y. Guo M. Ames S. Glockner S. Piantadosi S. Gabrielson E. Pridham G. DNA methylation markers and early recurrence in stage I lung cancer N. Engl. J. Med. 358 2008 1118 1128 18337602
  9. [9]Bradly D.P. Gattuso P. Pool M. Basu S. Liptay M. Bonomi P. Buckingham L. CDKN2A (p16) promoter hypermethylation influences the outcome in young lung cancer patients Diagn. Mol. Pathol. 21 2012 207 213 23111194
  10. [10]Sterlacci W. Tzankov A. Veits L. Zelger B. Bihl M.P. Foerster A. Augustin F. Fiegl M. Savic S. A comprehensive analysis of p16 expression, gene status, and promoter hypermethylation in surgically resected non-small cell lung carcinomas J. Thorac. Oncol. 6 2011 1649 1657 21857254
  11. [11]Inamura K. Diagnostic and therapeutic potential of MicroRNAs in lung cancer Cancers (Basel) 9 2017 49 PMC5447959 28486396
  12. [12]Zhang L. Huang P. Li Q. Wang D. Xu C.X. miR-134-5p promotes stage I lung adenocarcinoma metastasis and chemoresistance by targeting DAB2 Mol. Ther. Nucleic Acids 18 2019 627 637 31689617 PMC6838973
  13. [13]Fabbri M. Garzon R. Cimmino A. Liu Z. Zanesi N. Callegari E. Liu S. Alder H. Costinean S. Fernandez-Cymering C. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B Proc. Natl. Acad. Sci. U S A 104 2007 15805 15810 17890317 PMC2000384
  14. [14]Martini N. Bains M.S. Burt M.E. Zakowski M.F. McCormack P. Rusch V.W. Ginsberg R.J. Incidence of local recurrence and second primary tumors in resected stage I lung cancer J. Thorac. Cardiovasc. Surg. 109 1995 120 129 7815787
  15. [15]Chhabra R. Dubey R. Saini N. Cooperative and individualistic functions of the microRNAs in the miR-23a similar to 27a similar to 24-2 cluster and its implication in human diseases Mol. Cancer 9 2010 1 16 20815877 PMC2940846
  16. [16]Hua K. Chen Y.T. Chen C.F. Tang Y.S. Huang T.T. Lin Y.C. Yeh T.S. Huang K.H. Lee H.C. Hsu M.T. MicroRNA-23a/27a/24-2 cluster promotes gastric cancer cell proliferation synergistically Oncol. Lett. 16 2018 2319 2325 30008935 PMC6036456
  17. [17]Xu W.Y. Liu M.F. Peng X.L. Zhou P. Zhou J.W. Xu K. Xu H.X. Jiang S.S. miR-24-3p and miR-27a-3p promote cell proliferation in glioma cells via cooperative regulation of MXI1 Int. J. Oncol. 42 2013 757 766 23254855
  18. [18]Mazieres J. He B. You L. Xu Z. Lee A.Y. Mikami I. Reguart N. Rosell R. McCormick F. Jablons D.M. Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer Cancer Res. 64 2004 4717 4720 15256437
  19. [19]Toyooka K.O. Toyooka S. Virmani A.K. Sathyanarayana U.G. Euhus D.M. Gilcrease M. Minna J.D. Gazdar A.F. Loss of expression and aberrant methylation of the CDH13 (H-cadherin) gene in breast and lung carcinomas Cancer Res. 61 2001 4556 4560 11389090
  20. [20]Qu W.Q. Liu L. Yu Z. Clinical value of microRNA-23a upregulation in non-small cell lung cancer Int. J. Clin. Exp. Med. 8 2015 13598 13603 26550300 PMC4612985
  21. [21]Zhao G. Liu L. Zhao T. Jin S. Jiang S. Cao S. Han J. Xin Y. Dong Q. Liu X. Upregulation of miR-24 promotes cell proliferation by targeting NAIF1 in non-small cell lung cancer Tumour Biol. 36 2015 3693 3701 25725584
  22. [22]Eitan R. Kushnir M. Lithwick-Yanai G. David M.B. Hoshen M. Glezerman M. Hod M. Sabah G. Rosenwald S. Levavi H. Tumor microRNA expression patterns associated with resistance to platinum based chemotherapy and survival in ovarian cancer patients Gynecol. Oncol. 114 2009 253 259 19446316
  23. [23]Tang J. Zhao H. Cai H. Wu H. Diagnostic and prognostic potentials of microRNA-27a in osteosarcoma Biomed. Pharmacother. 71 2015 222 226 25960240
  24. [24]Xu X. Sun P.L. Li J.Z. Jheon S. Lee C.T. Chung J.H. Aberrant Wnt1/beta-catenin expression is an independent poor prognostic marker of non-small cell lung cancer after surgery J. Thorac. Oncol. 6 2011 716 724 21336184
  25. [25]Qi W. Chen J.Y. Cheng X.M. Huang J.N. Xiang T. Li Q.J. Long H.X. Zhu B. Targeting the Wnt-regulatory protein CTNNBIP1 by microRNA-214 enhances the stemness and self-renewal of cancer stem-like cells in lung adenocarcinomas Stem Cells 33 2015 3423 3436 26299367
  26. [26]Chang J.M. Tsai A.C. Huang W.R. Tseng R.C. The alteration of CTNNBIP1 in lung cancer Int. J. Mol. Sci. 20 2019 5684 PMC6888110 31766223
  27. [27]Lv L. Wan C. Chen B. Li M. Liu Y. Ni T. Yang Y. Liu Y. Cong X. Mao G. Nemo-like kinase (NLK) inhibits the progression of NSCLC via negatively modulating WNT signaling pathway J. Cell Biochem. 115 2014 81 92 23904219
  28. [28]Tang Q. Zhao H. Yang B. Li L. Shi Q. Jiang C. Liu H. WIF-1 gene inhibition and Wnt signal transduction pathway activation in NSCLC tumorigenesis Oncol. Lett. 13 2017 1183 1188 28454231 PMC5403432
  29. [29]Guo H. Zhou S. Tan L. Wu X. Wu Z. Ran R. Clinicopathological significance of WIF1 hypermethylation in NSCLC, a meta-analysis and literature review Oncotarget 8 2017 2550 2557 27911280 PMC5356219
  30. [30]Yamaguchi K. Shirakabe K. Shibuya H. Irie K. Oishi I. Ueno N. Taniguchi T. Nishida E. Matsumoto K. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction Science 270 1995 2008 2011 8533096
  31. [31]Yamada M. Ohnishi J. Ohkawara B. Iemura S. Satoh K. Hyodo-Miura J. Kawachi K. Natsume T. Shibuya H. NARF, an Nemo-like kinase (NLK)-associated ring finger protein regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF) J. Biol. Chem. 281 2006 20749 20760 16714285
  32. [32]Shibuya H. Yamaguchi K. Shirakabe K. Tonegawa A. Gotoh Y. Ueno N. Irie K. Nishida E. Matsumoto K. TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction Science 272 1996 1179 1182 8638164
  33. [33]Ohkawara B. Shirakabe K. Hyodo-Miura J. Matsuo R. Ueno N. Matsumoto K. Shibuya H. Role of the TAK1-NLK-STAT3 pathway in TGF-beta-mediated mesoderm induction Genes Dev. 18 2004 381 386 15004007 PMC359392
  34. [34]Hyodo-Miura J. Urushiyama S. Nagai S. Nishita M. Ueno N. Shibuya H. Involvement of NLK and Sox11 in neural induction in Xenopus development Genes Cells 7 2002 487 496 12047350
  35. [35]Wissmann C. Wild P.J. Kaiser S. Roepcke S. Stoehr R. Woenckhaus M. Kristiansen G. Hsieh J.C. Hofstaedter F. Hartmann A. WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer J. Pathol. 201 2003 204 212 14517837
  36. [36]Takahashi-Yanaga F. Sasaguri T. Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: inhibitors of the Wnt/beta-catenin signaling pathway as novel anticancer drugs J. Pharmacol. Sci. 109 2009 179 183 19179804
  37. [37]Kao S.H. Wang W.L. Chen C.Y. Chang Y.L. Wu Y.Y. Wang Y.T. Wang S.P. Nesvizhskii A.I. Chen Y.J. Hong T.M. GSK3beta controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug Oncogene 33 2014 3172 3182 23851495 PMC4096338
  38. [38]Lin R.K. Hsu H.S. Chang J.W. Chen C.Y. Chen J.T. Wang Y.C. Alteration of DNA methyltransferases contributes to 5'CpG methylation and poor prognosis in lung cancer Lung Cancer 55 2007 205 213 17140695
  39. [39]Yang H. Liu Y. Bai F. Zhang J.Y. Ma S.H. Liu J. Xu Z.D. Zhu H.G. Ling Z.Q. Ye D. Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation Oncogene 32 2013 663 669 22391558 PMC3897214
  40. [40]Ai L. Tao Q. Zhong S. Fields C.R. Kim W.J. Lee M.W. Cui Y. Brown K.D. Robertson K.D. Inactivation of Wnt inhibitory factor-1 (WIF1) expression by epigenetic silencing is a common event in breast cancer Carcinogenesis 27 2006 1341 1348 16501252
  41. [41]Liu Y. Zhu H. Zhang Z. Tu C. Yao D. Wen B. Jiang R. Li X. Yi P. Zhan J. Effects of a single transient transfection of ten-eleven translocation 1 catalytic domain on hepatocellular carcinoma PLoS One 13 2018 e0207139 30551127 PMC6294611
  42. [42]Lin T.S. Lee H. Chen R.A. Ho M.L. Lin C.Y. Chen Y.H. Tsai Y.Y. Chou M.C. Cheng Y.W. An association of DNMT3b protein expression with P16INK4a promoter hypermethylation in non-smoking female lung cancer with human papillomavirus infection Cancer Lett. 226 2005 77 84 16004934
  43. [43]Bai S. Ghoshal K. Jacob S.T. Identification of T-cadherin as a novel target of DNA methyltransferase 3B and its role in the suppression of nerve growth factor-mediated neurite outgrowth in PC12 cells J. Biol. Chem. 281 2006 13604 13611 16537533 PMC2241734
  44. [44]Yang L. Chen Y. Cui T. Knsel T. Zhang Q. Albring K.F. Huber O. Petersen I. Desmoplakin acts as a tumor suppressor by inhibition of the Wnt/β-catenin signaling pathway in human lung cancer Carcinogenesis 33 2012 1863 1870 22791817
  45. [45]Duruisseaux M. Esteller M. Lung cancer epigenetics: from knowledge to applications Semin. Cancer Biol. 51 2018 116 128 28919484
  46. [46]Dai F.Q. Li C.R. Fan X.Q. Tan L. Wang R.T. Jin H. miR-150-5p inhibits non-small-cell lung cancer metastasis and recurrence by targeting HMGA2 and beta-catenin signaling Mol. Ther. Nucleic Acids 16 2019 675 685 31121479 PMC6529773
  47. [47]Jin H. Jang Y. Cheng N. Li Q. Cui P.F. Zhou Z.W. Jiang H.L. Cho M.H. Westover K.D. Tan Q.Y. Restoration of mutant K-Ras repressed miR-199b inhibits K-Ras mutant non-small cell lung cancer progression J. Exp. Clin. Canc Res. 38 2019 165 PMC6466664 30987652
  48. [48]Xu C.X. Jere D. Jin H. Chang S.H. Chung Y.S. Shin J.Y. Kim J.E. Park S.J. Lee Y.H. Chae C.H. Poly(ester amine)-mediated, aerosol-delivered Akt1 small interfering RNA suppresses lung tumorigenesis Am. J. Respir. Crit. Care Med. 178 2008 60 73 18310482 PMC2441927
  49. [49]Nuovo G.J. In situ detection of microRNAs in paraffin embedded, formalin fixed tissues and the co-localization of their putative targets Methods 52 2010 307 315 20723602
  50. [50]Guo Z.Y. Hardin H. Montemayor-Garcia C. Asioli S. Righi A. Maletta F. Sapino A. Lloyd R.V. In situ hybridization analysis of miR-146b-5p and miR-21 in thyroid nodules: diagnostic implications Endocr. Pathol. 26 2015 157 163 25771986
  51. [51]Xu C.X. Jin H. Chung Y.S. Shin J.Y. Woo M.A. Lee K.H. Palmos G.N. Choi B.D. Cho M.H. Chondroitin sulfate extracted from the Styela clava tunic suppresses TNF-alpha-induced expression of inflammatory factors, VCAM-1 and iNOS by blocking Akt/NF-kappaB signal in JB6 cells Cancer Lett. 264 2008 93 100 18295395
  52. [52]Keene J.D. Komisarow J.M. Friedersdorf M.B. RIP-Chip: the isolation and identification of mRNAs, microRNAs and protein components of ribonucleoprotein complexes from cell extracts Nat. Protoc. 1 2006 302 307 17406249
  53. [53]Wang J. Walsh G. Liu D.D. Lee J.J. Mao L. Expression of Delta DNMT3B variants and its association with promoter methylation of p16 and RASSF1A in primary non-small cell lung cancer Cancer Res. 66 2006 8361 8366 16951144

Cited by

Sorted by citations

Authors
Fan, X., Tao, S., Li, Q., Deng, B., Tan, Q.-Y., & Jin, H.
Affiliations
Army Medical University (CN)
Corresponding author
Jin, Hua
ORCID
Venue
Molecular Therapy - Oncolytics
Publisher
Elsevier BV
Published
2022-03
Volume
24
Pages
205-217
ISSN
2372-7705 (ISSN-L)
DOI
10.1016/j.omto.2021.12.014
PMC
PMC8760463
OpenAlex
W4200020230
Cited by
26
References
0
Citations by year
2026: 4 · 2025: 7 · 2024: 6 · 2023: 5 · 2022: 4
FWCI
1.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy — Oncolytics (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81672283)
  • Natural Science Foundation of Chongqing (cstc2021jcyj-msxmX0350)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
  • Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords
early-stage non-small cell lung cancer, postoperative recurrence, Wnt/β-catenin signaling, DNA methylation, p16 promoter methylation, cancer stemness, metastasis, tumor suppressor gene silencing, recurrence biomarkers, microRNA therapeutic target

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