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Journal ArticleDOI

MiR-21 Indicates Poor Prognosis in Tongue Squamous Cell Carcinomas as an Apoptosis Inhibitor

15 Jun 2009-Clinical Cancer Research (Clinical Cancer Research)-Vol. 15, Iss: 12, pp 3998-4008
Abstract: Purpose: We aim to examine miR-21 expression in tongue squamous cell carcinomas (TSCC) and correlate it with patient clinical status, and to investigate its contribution to TSCC cell growth, apoptosis, and tumorigenesis. Experimental Design: MicroRNA profiling was done in 10 cases of TSCC with microarray. MiR-21 overexpression was quantitated with quantitative reverse transcription-PCR in 103 patients, and correlated to the pathoclinical status of the patients. Immunohistochemistry was used to examine the expression of TPM1 and PTEN , and terminal deoxynucleotidyl transferase–mediated dUTP labeling to evaluate apoptosis. Moreover, miR-21 antisense oligonucleotide (ASO) was transfected in SCC-15 and CAL27 cell lines, and tumor cell growth was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, adherent colony formation, and soft agar assay, whereas apoptosis was determined by Annexin V assay, cytochrome c release, and caspase 3 assay. Tumorigenesis was evaluated by xenografting SCC-15 cells in nude mice. Results: MiR-21 is overexpressed in TSCC relative to adjacent normal tissues. The level of miR-21 is reversely correlated with TPM1 and PTEN expression and apoptosis of cancer cells. Multivariate analysis showed that miR-21 expression is an independent prognostic factor indicating poor survival. Inhibiting miR-21 with ASO in TSCC cell lines reduces survival and anchorage-independent growth, and induces apoptosis in TSCC cell lines. Simultaneous silencing of TPM1 with siRNA only partially recapitulates the effect of miR-21 ASO. Furthermore, repeated injection of miR-21 ASO suppresses tumor formation in nude mice by reducing cell proliferation and inducing apoptosis. Conclusions: miR-21 is an independent prognostic indicator for TSCC, and may play a role in TSCC development by inhibiting cancer cell apoptosis partly via TPM1 silencing.
Citations
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Journal ArticleDOI
02 Sep 2010-Nature
TL;DR: It is shown that overexpression of miR-21 leads to a pre-B malignant lymphoid-like phenotype, demonstrating that mir-21 is a genuine oncogene and demonstrating efforts to treat human cancers through pharmacological inactivation of miRNAs such as miR -21.
Abstract: MicroRNAs (miRNAs) belong to a recently discovered class of small RNA molecules that regulate gene expression at the post-transcriptional level. miRNAs have crucial functions in the development and establishment of cell identity, and aberrant metabolism or expression of miRNAs has been linked to human diseases, including cancer. Components of the miRNA machinery and miRNAs themselves are involved in many cellular processes that are altered in cancer, such as differentiation, proliferation and apoptosis. Some miRNAs, referred to as oncomiRs, show differential expression levels in cancer and are able to affect cellular transformation, carcinogenesis and metastasis, acting either as oncogenes or tumour suppressors. The phenomenon of 'oncogene addiction' reveals that despite the multistep nature of tumorigenesis, targeting of certain single oncogenes can have therapeutic value, and the possibility of oncomiR addiction has been proposed but never demonstrated. MicroRNA-21 (miR-21) is a unique miRNA in that it is overexpressed in most tumour types analysed so far. Despite great interest in miR-21, most of the data implicating it in cancer have been obtained through miRNA profiling and limited in vitro functional assays. To explore the role of miR-21 in cancer in vivo, we used Cre and Tet-off technologies to generate mice conditionally expressing miR-21. Here we show that overexpression of miR-21 leads to a pre-B malignant lymphoid-like phenotype, demonstrating that mir-21 is a genuine oncogene. When miR-21 was inactivated, the tumours regressed completely in a few days, partly as a result of apoptosis. These results demonstrate that tumours can become addicted to oncomiRs and support efforts to treat human cancers through pharmacological inactivation of miRNAs such as miR-21.

920 citations

Journal ArticleDOI
TL;DR: Current understanding of mechanisms by which Akt and FoxOs regulate cell growth and survival that in turn offers opportunities for development of novel strategies to combat cancer is summarized.

892 citations

Journal ArticleDOI
TL;DR: A general overview of the connection between inflammation, microRNAs and cancer is provided and how improved understanding of these connections may provide novel preventive, diagnostic and therapeutic strategies to reduce the health burden of cancer is highlighted.
Abstract: Chronic inflammation and infection are major causes of cancer. There are continued improvements to our understanding of the molecular connections between inflammation and cancer. Key mediators of inflammation-induced cancer include nuclear factor kappa B, reactive oxygen and nitrogen species, inflammatory cytokines, prostaglandins and specific microRNAs. The collective activity of these mediators is largely responsible for either a pro-tumorigenic or anti-tumorigenic inflammatory response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. As our understanding grows, inflammatory mediators will provide opportunities to develop novel diagnostic and therapeutic strategies. In this review, we provide a general overview of the connection between inflammation, microRNAs and cancer and highlight how our improved understanding of these connections may provide novel preventive, diagnostic and therapeutic strategies to reduce the health burden of cancer.

607 citations

Journal ArticleDOI
TL;DR: In this paper, the role of miR-21 in non-small cell lung cancer (NSCLC) and to clarify the regulation of PTEN by miR21 and determine mechanisms of this regulation were identified.

519 citations


Cites background from "MiR-21 Indicates Poor Prognosis in ..."

  • ...Its expression is obviously up-regulated in diverse types of malignancies such as glioblastoma multiforme [34], breast cancer [11,13], lung cancer [13,14,35–37], esophageal cancer [17], gastrointestinal cancer [13,38,39], hepatocellular cancer [16], cholangiocarcinoma [15], pancreatic cancer [13,19], prostate cancer [13], bladder cancer [24], ovarian cancer [20], NK-cell lymphoma [21], laryngeal carcinoma [22], and tongue squamous cell carcinomas [23]....

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References
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Journal ArticleDOI
23 Jan 2004-Cell
TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.

32,946 citations


"MiR-21 Indicates Poor Prognosis in ..." refers background in this paper

  • ...Numbers marked on top (1-10) represent the number of each specimen....

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  • ...They regulate gene expression by repressing mRNA translation or cleaving target mRNA (5, 6)....

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Journal ArticleDOI
TL;DR: There are striking variations in the risk of different cancers by geographic area, most of the international variation is due to exposure to known or suspected risk factors related to lifestyle or environment, and provides a clear challenge to prevention.
Abstract: Estimates of the worldwide incidence, mortality and prevalence of 26 cancers in the year 2002 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. The results are presented here in summary form, including the geographic variation between 20 large "areas" of the world. Overall, there were 10.9 million new cases, 6.7 million deaths, and 24.6 million persons alive with cancer (within three years of diagnosis). The most commonly diagnosed cancers are lung (1.35 million), breast (1.15 million), and colorectal (1 million); the most common causes of cancer death are lung cancer (1.18 million deaths), stomach cancer (700,000 deaths), and liver cancer (598,000 deaths). The most prevalent cancer in the world is breast cancer (4.4 million survivors up to 5 years following diagnosis). There are striking variations in the risk of different cancers by geographic area. Most of the international variation is due to exposure to known or suspected risk factors related to lifestyle or environment, and provides a clear challenge to prevention.

17,730 citations

Journal ArticleDOI
03 Dec 1993-Cell
TL;DR: Two small lin-4 transcripts of approximately 22 and 61 nt were identified in C. elegans and found to contain sequences complementary to a repeated sequence element in the 3' untranslated region (UTR) of lin-14 mRNA, suggesting that lin- 4 regulates lin- 14 translation via an antisense RNA-RNA interaction.

11,932 citations


"MiR-21 Indicates Poor Prognosis in ..." refers background in this paper

  • ...Numbers marked on top (1-10) represent the number of each specimen....

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Journal ArticleDOI
TL;DR: While the absolute number of cancer deaths decreased for the second consecutive year in the United States, much progress has been made in reducing mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years.
Abstract: Each year, the American Cancer Society (ACS) estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics This report considers incidence data through 2003 and mortality data through 2004 Incidence and death rates are age-standardized to the 2000 US standard million population A total of 1,444,920 new cancer cases and 559,650 deaths for cancers are projected to occur in the United States in 2007 Notable trends in cancer incidence and mortality rates include stabilization of the age-standardized, delay-adjusted incidence rates for all cancers combined in men from 1995 through 2003; a continuing increase in the incidence rate by 03% per year in women; and a 136% total decrease in age-standardized cancer death rates among men and women combined between 1991 and 2004 This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends While the absolute number of cancer deaths decreased for the second consecutive year in the United States (by more than 3,000 from 2003 to 2004) and much progress has been made in reducing mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population

7,446 citations

Journal ArticleDOI
TL;DR: It is shown here that miRNAs are present in human plasma in a remarkably stable form that is protected from endogenous RNase activity and established the measurement of tumor-derived mi RNAs in serum or plasma as an important approach for the blood-based detection of human cancer.
Abstract: Improved approaches for the detection of common epithelial malignancies are urgently needed to reduce the worldwide morbidity and mortality caused by cancer. MicroRNAs (miRNAs) are small (≈22 nt) regulatory RNAs that are frequently dysregulated in cancer and have shown promise as tissue-based markers for cancer classification and prognostication. We show here that miRNAs are present in human plasma in a remarkably stable form that is protected from endogenous RNase activity. miRNAs originating from human prostate cancer xenografts enter the circulation, are readily measured in plasma, and can robustly distinguish xenografted mice from controls. This concept extends to cancer in humans, where serum levels of miR-141 (a miRNA expressed in prostate cancer) can distinguish patients with prostate cancer from healthy controls. Our results establish the measurement of tumor-derived miRNAs in serum or plasma as an important approach for the blood-based detection of human cancer.

7,296 citations


"MiR-21 Indicates Poor Prognosis in ..." refers background in this paper

  • ...Changes of miRNA profile in many types of body fluids may reflect potential physiologic and/or pathologic conditions (38, 39), and thus, may be applicable in clinics....

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