CoChat
Sign Up
Cited by 2,773MicroRNA in disease regulationCancer-related molecular mechanisms researchMechanisms of cancer metastasis

MicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular Cancer

Open access
Meng, Fanyin, Henson, Roger, Wehbe–Janek, Hania, Ghoshal, Kalpana, Jacob, Samson T., Patel, Tushar·2007·Gastroenterology
DOI 10.1053/j.gastro.2007.05.022PMC PMC4285346
Open this paper in CoChat — free account

Abstract

Background and aims microRNAs (miRNAs) are short noncoding RNAs that regulate gene expression negatively. Although a role for aberrant miRNA expression in cancer has been postulated, the pathophysiologic role and relevance of aberrantly expressed miRNA to tumor biology has not been established. Methods We evaluated the expression of miRNA in human hepatocellular cancer (HCC) by expression profiling, and defined a target gene and biologically functional effect of an up-regulated miRNA. Results miR-21 was noted to be highly overexpressed in HCC tumors and cell lines in expression profiling studies using a miRNA microarray. Inhibition of miR-21 in cultured HCC cells increased expression of the phosphatase and tensin homolog (PTEN) tumor suppressor, and decreased tumor cell proliferation, migration, and invasion. In contrast-enhanced miR-21 expression by transfection with precursor miR-21 increased tumor cell proliferation, migration, and invasion. Moreover, an increase in cell migration was observed in normal human hepatocytes transfected with precursor miR-21. PTEN was shown to be a direct target of miR-21, and to contribute to miR-21 effects on cell invasion. Modulation of miR-21 altered focal adhesion kinase phosphorylation and expression of matrix metalloproteases 2 and 9, both downstream mediators of PTEN involved in cell migration and invasion. Conclusions Aberrant expression of miR-21 can contribute to HCC growth and spread by modulating PTEN expression and PTEN-dependent pathways involved in mediating phenotypic characteristics of cancer cells such as cell growth, migration, and invasion.

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 · 10.1053/j.gastro.2007.05.022

Cites

2 of 2 references verified0 citation errors · 0 not checkable

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-21 functions at least in part by targeting a host of pro-apoptotic genes.

    “miR-21 functions–at least in part–by targeting a host of pro-apoptotic genes [13, 14].”

    From MicroRNA‐21 protects neurons from ischemic death (2010) · cites this paper as [14]

    The Results identify PTEN as a direct target of miR-21, and the Discussion reports anti-apoptotic effects of miR-21 in other cancers. But this paper does not show that miR-21 targets a host of pro-apoptotic genes; it identifies one direct target and only speculates about others. Page numbers were not provided in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Several components of the PI3K pathway, including PTEN and PIK3R1, have been suggested as miR-21 target genes; however, miR-21 over-expression did not alter PTEN and PIK3R1 protein expression or Akt phosphorylation.

    “Several components of the PI3K pathway, including PTEN and PIK3R1, have been suggested as miR-21 target genes (Meng et al., 2007); however, miR-21 over-expression did not alter PTEN and PIK3R1 protein expression or Akt phosphorylation (Figure S3B).”

    From Modulation of K-Ras-Dependent Lung Tumorigenesis by MicroRNA-21 (2010) · cites this paper as Meng et al., 2007

    The Results identify PTEN as a miR-21 target, and the Discussion places PTEN in the PI3K pathway. The passages do not identify PIK3R1 as a miR-21 target. The statement that over-expression did not alter protein expression or Akt phosphorylation is attributed to the citing paper’s Figure S3B, not to Meng et al. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • There is ample evidence that miR-21 expression really is altered in many disease states.

    “One important point about all of these studies is that there is ample evidence that miR-21 expression really is altered in many disease states [11, 20, 77, 78].”

    From miR-21: a non‐specific biomarker of all maladies (2021) · cites this paper as [11]

  • miR-21 has been implicated in cellular proliferation, apoptosis, and migration in carcinogenesis.

    “This microRNA has been implicated in various aspects of carcinogenesis, including cellular proliferation, apoptosis, and migration.”

    From MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators (2008) · cites this paper as [44]

  • Elevated miR-21 expression has been causally linked to proliferation, apoptosis, and migration of several cancer cell lines.

    “Elevated miR-21 expression has been causally linked to proliferation, apoptosis, and migration of several cancer cell lines (1, 5, 44, 60).”

    From MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators (2008) · cites this paper as [44]

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

Flagged first, then by citations

Research works printed but not linked: 28

  1. [1]El Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–750. doi: 10.1056/NEJM199903113401001. [DOI] [PubMed] [Google Scholar] · DOI
  2. [2]Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31:339–346. doi: 10.1038/ng0802-339. [DOI] [PubMed] [Google Scholar] · DOI
  3. [3]Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70. doi: 10.1016/s0092-8674(00)81683-9. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  4. [4]Thorgeirsson SS, Lee JS, Grisham JW. Functional genomics of hepatocellular carcinoma. Hepatology. 2006;43:S145–S150. doi: 10.1002/hep.21063. [DOI] [PubMed] [Google Scholar] · DOI
  5. [5]Calin GA, Croce CM. MicroRNA-cancer connection: the beginning of a new tale. Cancer Res. 2006;66:7390–7394. doi: 10.1158/0008-5472.CAN-06-0800. [DOI] [PubMed] [Google Scholar] · DOI
  6. [6]Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–269. doi: 10.1038/nrc1840. [DOI] [PubMed] [Google Scholar] · DOI
  7. [7]McManus MT. MicroRNAs and cancer. Semin Cancer Biol. 2003;13:253–258. doi: 10.1016/s1044-579x(03)00038-5. [DOI] [PubMed] [Google Scholar] · DOI
  8. [8]Kutay H, Bai S, Datta J, Motiwala T, Pogribny I, Frankel W, Jacob ST, Ghoshal K. Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem. 2006;15:671–678. doi: 10.1002/jcb.20982. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted] · DOI · Paper page
  9. [9]Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T, Shimotohno K. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene. 2006;25:2537–2545. doi: 10.1038/sj.onc.1209283. [DOI] [PubMed] [Google Scholar] · DOI
  10. [11]Saeed AI, Sharov V, White J, Li J, Liang W, Bhagabati N, Braisted J, Klapa M, Currier T, Thiagarajan M, Sturn A, Snuffin M, Rezantsev A, Popov D, Ryltsov A, Kostukovich E, Borisovsky I, Liu Z, Vinsavich A, Trush V, Quackenbush J. TM4: a free, open-source system for microarray data management and analysis. Biotechniques. 2003;34:374–378. doi: 10.2144/03342mt01. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  11. [12]Meng F, Yamagiwa Y, Ueno Y, Patel T. Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes. J Hepatol. 2006;44:1055–1065. doi: 10.1016/j.jhep.2005.10.030. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  12. [13]Park J, Tadlock L, Gores GJ, Patel T. Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line. Hepatology. 1999;30:1128–1133. doi: 10.1002/hep.510300522. [DOI] [PubMed] [Google Scholar] · DOI
  13. [14]Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65:6029–6033. doi: 10.1158/0008-5472.CAN-05-0137. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  14. [15]Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006;103:2257–2261. doi: 10.1073/pnas.0510565103. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  15. [16]Kim RH, Mak TW. Tumours and tremors: how PTEN regulation underlies both. Br J Cancer. 2006;94:620–624. doi: 10.1038/sj.bjc.6602994. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  16. [17]Gautam A, Li ZR, Bepler G. RRM1-induced metastasis suppression through PTEN-regulated pathways. Oncogene. 2003;22:2135–2142. doi: 10.1038/sj.onc.1206232. [DOI] [PubMed] [Google Scholar] · DOI
  17. [18]Park MJ, Kim MS, Park IC, Kang HS, Yoo H, Park SH, Rhee CH, Hong SI, Lee SH. PTEN suppresses hyaluronic acid-induced matrix metalloproteinase-9 expression in U87MG glioblastoma cells through focal adhesion kinase dephosphorylation. Cancer Res. 2002;62:6318–6322. [PubMed] [Google Scholar]
  18. [19]Akahane T, Akahane M, Shah A, Connor CM, Thorgeirsson UP. TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms. Exp Cell Res. 2004;301:158–167. doi: 10.1016/j.yexcr.2004.08.002. [DOI] [PubMed] [Google Scholar] · DOI
  19. [20]Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, Mizuno K, Hasegawa G, Kishimoto H, Iizuka M, Naito M, Enomoto K, Watanabe S, Mak TW, Nakano T. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest. 2004;113:1774–1783. doi: 10.1172/JCI20513. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  20. [21]Cheng AM, Byrom MW, Shelton J, Ford LP. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res. 2005;33:1290–1297. doi: 10.1093/nar/gki200. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  21. [22]Wan XW, Jiang M, Cao HF, He YQ, Liu SQ, Qiu XH, Wu MC, Wang HY. The alteration of PTEN tumor suppressor expression and its association with the histopathological features of human primary hepatocellular carcinoma. J Cancer Res Clin Oncol. 2003;129:100–106. doi: 10.1007/s00432-002-0410-x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  22. [23]Hu TH, Huang CC, Lin PR, Chang HW, Ger LP, Lin YW, Changchien CS, Lee CM, Tai MH. Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma. Cancer. 2003;97:1929–1940. doi: 10.1002/cncr.11266. [DOI] [PubMed] [Google Scholar] · DOI
  23. [24]Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science. 1998;280:1614–1617. doi: 10.1126/science.280.5369.1614. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  24. [25]Itoh S, Maeda T, Shimada M, Aishima S, Shirabe K, Tanaka S, Maehara Y. Role of expression of focal adhesion kinase in progression of hepatocellular carcinoma. Clin Cancer Res. 2004;10:2812–2817. doi: 10.1158/1078-0432.ccr-1046-03. [DOI] [PubMed] [Google Scholar] · DOI
  25. [26]Fujii T, Koshikawa K, Nomoto S, Okochi O, Kaneko T, Inoue S, Yatabe Y, Takeda S, Nakao A. Focal adhesion kinase is overexpressed in hepatocellular carcinoma and can be served as an independent prognostic factor. J Hepatol. 2004;41:104–111. doi: 10.1016/j.jhep.2004.03.029. [DOI] [PubMed] [Google Scholar] · DOI
  26. [27]Yamamoto H, Itoh F, Adachi Y, Sakamoto H, Adachi M, Hinoda Y, Imai K. Relation of enhanced secretion of active matrix metalloproteinases with tumor spread in human hepatocellular carcinoma. Gastroenterology. 1997;112:1290–1296. doi: 10.1016/s0016-5085(97)70143-4. [DOI] [PubMed] [Google Scholar] · DOI
  27. [28]Arii S, Mise M, Harada T, Furutani M, Ishigami S, Niwano M, Mizumoto M, Fukumoto M, Imamura M. Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology. 1996;24:316–322. doi: 10.1053/jhep.1996.v24.pm0008690399. [DOI] [PubMed] [Google Scholar] · DOI
  28. [30]Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, Watts L, Booten SL, Graham M, McKay R, Subramaniam A, Propp S, Lollo BA, Freier S, Bennett CF, Bhanot S, Monia BP. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006;3:87–98. doi: 10.1016/j.cmet.2006.01.005. [DOI] [PubMed] [Google Scholar] · DOI · Paper page

Cited by

Sorted by citations

Authors
Meng, F., Henson, R., Wehbe–Janek, H., Ghoshal, K., Jacob, S. T., & Patel, T.
Affiliations
  • Texas A&M University System (US)
  • The Ohio State University (US)
Corresponding author
Patel, Tushar
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2007-08
Volume
133
Issue
2
Pages
647-658
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2007.05.022
PMC
PMC4285346
OpenAlex
W2000093333
Cited by
2,773
References
2
Citations by year
2026: 50 · 2025: 54 · 2024: 66 · 2023: 88 · 2022: 106 · 2021: 122 · 2020: 138 · 2019: 124 · 2018: 138 · 2017: 160 · 2016: 183 · 2015: 222 · 2014: 222 · 2013: 210 · 2012: 208
FWCI
55.31
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (R21CA122694, CA122694)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-069370, R01DK069370)
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords
miR-21, PTEN, hepatocellular carcinoma, tumor suppressor regulation, cell proliferation, cell migration, tumor invasion, focal adhesion kinase phosphorylation, MMP-2, MMP-9, miRNA target genes
MeSH terms
Cell Movement, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Neoplasm Invasiveness, Phosphorylation, RNA, Messenger, Transfection, Up-Regulation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Oligonucleotides, Antisense, Oligonucleotide Array Sequence Analysis, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Gene Expression Profiling, RNA, Small Interfering, MicroRNAs, Cell Line, Tumor, Cell Proliferation, PTEN Phosphohydrolase, Focal Adhesion Protein-Tyrosine Kinases

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