miR-221/222 overexpession in human glioblastoma increases invasiveness by targeting the protein phosphate PTPμ

Abstract

Glioblastoma is the most frequent brain tumor in adults and is the most lethal form of human cancer. Despite the improvements in treatments, survival of patients remains poor. In order to identify microRNAs (miRs) involved in glioma tumorigenesis, we evaluated, by a miRarray, differential expression of miRs in the tumorigenic glioma LN-18, LN-229 and U87MG cells compared with the non-tumorigenic T98G cells. Among different miRs we focused our attention on miR-221 and -222. We demonstrated the presence of a binding site for these two miRs in the 3′ untranslated region of the protein tyrosine phosphatase μ (PTPμ). Previous studies indicated that PTPμ suppresses cell migration and is downregulated in glioblastoma. Significantly, we found that miR-221 and -222 over-expression induced a downregulation of PTPμ as analyzed by both western blot and real-time PCR. Furthermore, miR-222 and -221 induced an increase in cell migration and growth in soft agar in glioma cells. Interestingly, the re-expression of PTPμ gene was able to revert the miR-222 and -221 effects on cell migration. Furthermore, we found an inverse correlation between miR-221 and -222 and PTPμ in human glioma cancer samples. In conclusion, our results suggest that miR-221 and -222 regulate glioma tumorigenesis at least in part through the control of PTPμ protein expression.

Regulation of Mirna Pathway and Roles of Micrornas in Tumorigenesis and Metastasis

“…Consistently, the reexpression of PTPμ gene is able to revert the miR-222 and -221 effects on cell migration. The miR-221/222 overexpession and invasiveness increase is further confirmed in human glioma cancer samples [127], suggesting that the miR-221 and -222 regulate glioma tumorigenesis at least in part through the control of PTPμ protein expression. Transcriptionally induced by Twist 1, a transcription factor, miR-10b has been known for its promotion to breast cancer metastasis and epithelialmesenchymal transition evidenced by the fact that the miR-10b is highly expressed in metastatic breast cancer cells and positively regulates cell migration and invasion in a way that miR-10b inhibits translation of its direct target mRNA encoding for homeobox D10 and in turn activates another well-characterized pro-metastatic gene, RHOC [128].…”

Downregulation of miR-544 in tissue, but not in serum, is a novel biomarker of malignant transformation in glioma

“…miR-181a and miR-181b were observed as tumor suppressors that inhibit growth and induce the apoptosis of glioma cells (19). The expression of miR-221 and 222 were upregulated in human glioblastoma and they induced an increase in cell migration and growth by targeting the protein phosphate PTPµ, whereas let-7 reduced the in vitro proliferation and migration of glioma cells (20,21).…”

The role of micro-RNA in the regulation of signal pathways in gliomas

“…Следует отметить, что роль miR-221/222 в патогенезе глиом/глиобластом активно изучается. С помощью иммуноблоттинга и ОТ-ПЦР было показано, что гиперэкспрессия miR-221/222, характерная для клеток глиом, снижает уровень PTPm (protein tyrosine phosphatase, receptor type M) -фермента, подавляющего клеточную миграцию [46], и MGMT (O-6-methylguanine-DNA methyltransferase), участвующую в ДНК-репарации. Это, с одной стороны, приводит к усилению темозоломид-индуцированной гибели клеток, но, с другой стороны, к увеличению повреждений ДНК и хромосомных аберраций в клетках мозга [47].…”

“…[45]. Сайленсинг гена MGMT может быть также обусловлен гиперметилированием CpG-островков, что характерно для глиом [95] [ [45][46][47], [95] Если для исследования необходимо сделать полногеномный анализ дифференциальной экспрессии транскриптома, то относительно дешёвым и менее подверженным ошибкам методом является гибридизация на микрочипах (miRNA microarray).…”