E2F1-Regulated MicroRNAs Impair TGFβ-Dependent Cell-Cycle Arrest and Apoptosis in Gastric Cancer

Abstract

Deregulation of E2F1 activity and resistance to TGFbeta are hallmarks of gastric cancer. MicroRNAs (miRNAs) are small noncoding RNAs frequently misregulated in human malignancies. Here we provide evidence that the miR-106b-25 cluster, upregulated in a subset of human gastric tumors, is activated by E2F1 in parallel with its host gene, Mcm7. In turn, miR-106b and miR-93 regulate E2F1 expression, establishing a miRNA-directed negative feedback loop. Furthermore, upregulation of these miRNAs impairs the TGFbeta tumor suppressor pathway, interfering with the expression of CDKN1A (p21(Waf1/Cip1)) and BCL2L11 (Bim). Together, these results suggest that the miR-106b-25 cluster is involved in E2F1 posttranscriptional regulation and may play a key role in the development of TGFbeta resistance in gastric cancer.

Analysis of the miRNA–mRNA–lncRNA networks in ER+ and ER− breast cancer cell lines

“…Overexpression of the miR‐17‐92 cluster is observed in a variety of cancers, including small‐cell lung cancer, colon cancer, neuroblastomas, medulloblastoma and gastric cancer 35, 36, 37, 38. Calvano et al .…”

Loss of p21Sdi1 expression in senescent cells after DNA damage accompanied with increase of miR-93 expression and reduced p53 interaction with p21Sdi1 gene promoter

“…Indeed, multiple microRNAs in miR-106 family and related miRNAs rescue Ras-induced senescence and induce colony formation in soft agar in HMECs via downregulation of p21 by miR-106/302 [28]. They are associated with progression of variable tumors; miR-106a and miR-106b in gastric adenocarcinoma [29], miR-17-5p and miR-372 in squamous cell carcinoma [30], miR-372 and miR-373 in testicular germ cell tumors [10], and miR-373 with miR-520c in the metastatic tumors [31]. Moreover, inactivation of p21 and p16 INK4a facilitates immortalization and anchorage independent growth of mouse fibroblasts [11].…”

Overexpression of miR-370 and downregulation of its novel target TGFβ-RII contribute to the progression of gastric carcinoma

“…It causes 12% of all cancer-related deaths and the toll is estimated to be one million deaths each year (Petrocca et al, 2008;Zhang et al, 2008). Identification of the molecular alterations involved in the pathogenesis of GC may help with the developing diagnostic markers that aid therapeutic intervention (Motoyama et al, 2008;Lo et al, 2009).…”

“…MicroRNAs (miRNAs) are small non-coding RNAs involved in the regulation of translation and in the degradation of target mRNAs (Dalmay and Edwards, 2006;Bartel, 2009). Since a miRNA is able to regulate hundreds of genes (Selbach et al, 2008), it is thought that miRNAs may be involved in the regulation of expression of up to 30% of human genes (Petrocca et al, 2008). Understanding the expression profile of miRNAs and the function of individual miRNAs will help with the validation of specific miRNA as crucial diagnostic markers and also provide therapeutic targets for cancer treatment.…”