Let-7 expression defines two differentiation stages of cancer

Abstract

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 Ecadherin 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.HMGA2 ͉ miRNA ͉ ovarian cancer ͉ tumor progression ͉ supercluster

New insights into apoptosis signaling by Apo2L/TRAIL

“…Furthermore, high and low levels of the miRNA let-7 were found in epithelial type II cells and mesenchymal type I cells, respectively, while let-7 expression inversely correlated with disease progression in ovarian cancer (Shell et al, 2007). Thus, it has been proposed that cancer cells with a type II versus type I response to FasL may represent different stages of carcinogenesis that resemble the epithelial-mesenchymal transition (Shell et al, 2007). Whether the same applies to apoptotic signaling in response to Apo2L/TRAIL requires further study.…”

“…Analysis of sensitivity to FasL in tumor cell lines suggests that type I cells tend to express mesenchymal-like genes, whereas type II cells express epithelial-like genes (Algeciras-Schimnich et al, 2003). Furthermore, high and low levels of the miRNA let-7 were found in epithelial type II cells and mesenchymal type I cells, respectively, while let-7 expression inversely correlated with disease progression in ovarian cancer (Shell et al, 2007). Thus, it has been proposed that cancer cells with a type II versus type I response to FasL may represent different stages of carcinogenesis that resemble the epithelial-mesenchymal transition (Shell et al, 2007).…”

Genetic modulation of the Let-7 microRNA binding to KRAS 3′-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab–irinotecan

“…At the moment, we could hypothesize that some clonal selection may occur in the tumor and it favors less differentiated and more aggressive clones that harbor both KRAS mutation and the KRAS 3 0 -UTR LCS6 G-allele variant. 18,19 In addition, an intriguing hypothesis is that the KRAS 3 0 -UTR LCS6 G-allele promotes some mechanisms in the colorectal cancer microenvironment that facilitate the development of KRAS mutations.…”

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

“…Let-7 family members also target HMGA2, an oncogene known for its involvement in promoting the epithelial-mesenchymal transition (EMT) (Shell et al, 2007). miR-15 and miR-16 promote apoptosis by suppressing expression of the antiapoptotic Bcl-2 protein and are commonly deleted in chronic lymphocytic leukemia (CLL), which leads to high levels of Bcl-2 expression (a prognostic indicator in CLL) (Volinia et al, 2006;Garcia-Manero et al, 2008).…”