Let-7 expression defines two differentiation stages of cancer.
The early phases of carcinogenesis resemble embryonic development, often involving the reexpression of embryonic mesenchymal genes. The NCI60 panel of human tumor cell lines can genetically be subdivided into two superclusters (SCs) that correspond to CD95 Type I and II cells. SC1 cells are characterized by a mesenchymal and SC2 cells by an epithelial gene signature, suggesting that SC1 cells represent less differentiated, advanced stages of cancer. miRNAs are small 20- to 22-nucleotide-long noncoding RNAs that inhibit gene expression at the posttranscriptional level. By performing miRNA expression analysis on 10 Type I and 10 Type II cells, we have determined that SC1 cells express low and SC2 cells high levels of the miRNA let-7, respectively, suggesting that let-7 is a marker for less advanced cancers. Expression of the let-7 target high-mobility group A2 (HMGA2), an early embryonic gene, but not of classical epithelial or mesenchymal markers such as E-cadherin or vimentin, inversely correlated with let-7 expression in SC1 and SC2 cells. Using ovarian cancer as a model, we demonstrate that expression of let-7 and HMGA2 is a better predictor of prognosis than classical markers such as E-cadherin, vimentin, and Snail. These data identify loss of let-7 expression as a marker for less differentiated cancer.
Shell
Scott
S
Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
Park
Sun-Mi
SM
Radjabi
Amir Reza
AR
Schickel
Robert
R
Kistner
Emily O
EO
Jewell
David A
DA
Feig
Christine
C
Lengyel
Ernst
E
Peter
Marcus E
ME
D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000096:biosynthesis / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D011237:Predictive Value of Tests
D014408:Biomarkers, Tumor; D025743:HMGA2 Protein; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human