Temozolomide resistance in glioblastoma occurs by miRNA-9-targeted PTCH1, independent of sonic hedgehog level

Abstract

Glioblastoma Multiforme (GBM), the most common and lethal adult primary tumor of the brain, showed a link between Sonic Hedgehog (SHH) pathway in the resistance to temozolomide (TMZ). PTCH1, the SHH receptor, can tonically represses signaling by endocytosis. We asked how the decrease in PTCH1 in GBM cells could lead to TMZ-resistance. TMZ resistant GBM cells have increased PTCH1 mRNA and reduced protein. Knockdown of Dicer, a Type III RNAase, indicated that miRNAs can explain the decreased PTCH1 in TMZ resistant cells. Computational studies, real-time PCR, reporter gene studies, western blots, target protector oligos and ectopic expression identified miR-9 as the target of PTCH1 in resistant GBM cells with concomitant activation of SHH signaling. MiR-9 mediated increases in the drug efflux transporters, MDR1 and ABCG2. MiR-9 was increased in the tissues from GBM patients and in an early passage GBM cell line from a patient with recurrent GBM but not from a naïve patient. Pharmacological inhibition of SHH signaling sensitized the GBM cells to TMZ. Taken together, miR-9 targets PTCH1 in GBM cells by a SHH-independent method in GBM cells for TMZ resistance. The identified pathways could lead to new strategies to target GBM with combinations of drugs.

Temozolomide competes for P-glycoprotein and contributes to chemoresistance in glioblastoma cells

“…We have recently reported on the expression of miRNA-9 in GBM cells and its involvement with TMZ resistance, through upregulated expression of MDR1 [12]. These studies were done at both the transcriptional and post-translational level.…”

Network-Based Method for Identifying Co-Regeneration Genes in Bone, Dentin, Nerve and Vessel Tissues

“…Similarly, PTCH1, as an inferred co-regeneration gene of bone and dentin, has also been validated to contribute to the regeneration of dentin and vessels based on recent publications. Such gene encodes a receptor for sonic hedgehog as we have analyzed above participating in the hedgehog signaling pathway [43]. Considering that hedgehog signaling pathway has been confirmed to contribute to the co-regeneration of dentin and vessel [43], it is quite reasonable to regard PTCH1 as a co-regenerative gene for dentin and vessels.…”

“…Such gene encodes a receptor for sonic hedgehog as we have analyzed above participating in the hedgehog signaling pathway [43]. Considering that hedgehog signaling pathway has been confirmed to contribute to the co-regeneration of dentin and vessel [43], it is quite reasonable to regard PTCH1 as a co-regenerative gene for dentin and vessels. Apart from such two analyzed genes, we also obtained six additional genes for the co-regeneration of dentin and vessel.…”

“…The last gene turns out to be PTCH1 (ENSP00000332353). According to recent publications, such gene has been reported to encode a functional receptor for sonic hedgehog, a secreted development and tumorigenesis associated molecule [43,44]. As a functional component of hedgehog signaling pathway [45], PTCH1 has been widely reported to participate in the regeneration of bone in human beings and various animal models [46,47].…”

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

“…показал, что молекула PTCH1, блокирующая активацию Shh-пути, является мишенью miR-9 при глиобластоме. Поэтому гиперактивация miR-9 может способствовать резистентности к противоопухолевому препарату темозоломиду, а ингибирование miR-9 в этом свете предстает как потенциальный терапевтический способ повышения химиочувствительности [26]. В связи с характерной мутацией R132H IDH1 можно отметить, что некоторые микро-РНК, регулирующие Hh-сигналинг, а именно miR-9 и miR-324 входят в группу из 23 miR, специфических именно для IDH1-мутированных глиобластом, как показало исследование экспрессии микро-РНК 470 образцов глиобластом из базы данных TCGA (The Cancer Genome Atlas).…”