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Long non-coding RNA MALAT1 as a key target in pathogenesis of glioblastoma. Janus faces or Achilles' heal?
Yucel Baspinar1, Ilhan Elmaci2, Aysel Ozpinar3
1Department of Pharmacy, Ege University, Turkey.
Abstract:
Glioblastomas (GBMs) are primary brain tumors with extremely bad prognosis and therefore; discovery of novel regulators of their pathology is of immense importance. LncRNAs (long noncoding RNAs) regulate nuclear structure, embryonic pluripotency, cell differentiation, development and carcinogenesis. Many lncRNAs have weak evolutionary conservation; however, a nuclear lncRNA, MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), is exceptionally conserved and is among the most abundant lncRNAs in benign tissues. The majority of cell culture studies and clinico-epidemiological studies demonstrated that MALAT1 acts a tumor promoter in GBMs and inhibition of MALAT1 suppressed tumor growth in various preclinical models of GBM. MALAT1 involves in stemness of GBM cells by regulating SOX2, nestin and members of WNT pathway. MALAT1 induces protective autophagy and suppresses apoptosis in GBM cells via sponging miRNA-101 and increases temozolomide chemoresistance via enhancing epithelial-mesenchymal transition, suppressing miR-203 and promoting thymidilate synthase. Moreover, knockdown of MALAT1 expression enhances blood-brain tumor barrier permeability via miR-140, which may provide a double benefit of MALAT1 suppression by increasing the delivery of chemotherapy agents into the GBM tissues. On the other hand, there also exist some cell culture and animal studies showing that MALAT1 acts as a tumor suppressor in GBMs by suppression of ERK/MAPK and MMP2 signaling and by repression of miR-155 with subsequent increase of FBXW7. Whether protective or detrimental, MALAT1 seems to be an important component of GBM pathogenesis and hence; novels studies are needed in versatile models, including many different primary GBM cultures, orthotopic and xenogreft in vivo models and transgenic mice.
Insights
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a dual role in glioblastoma (GBM) pathology, acting as both a tumor promoter and suppressor. Further research in diverse models is crucial to understand its complex role in GBM.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Glioblastomas (GBMs) are aggressive primary brain tumors with poor prognoses, necessitating the identification of novel therapeutic targets.
- Long noncoding RNAs (lncRNAs) are emerging regulators of cellular processes, including carcinogenesis, with MALAT1 being a notably conserved and abundant example.
- MALAT1's role in GBM is complex, with studies suggesting both tumor-promoting and tumor-suppressing functions.
Purpose of the Study:
- To review the multifaceted role of the lncRNA MALAT1 in glioblastoma pathogenesis.
- To explore MALAT1's involvement in GBM stemness, chemoresistance, and blood-brain barrier permeability.
- To highlight the contradictory findings regarding MALAT1's function and emphasize the need for further investigation.
Main Methods:
- Review of existing cell culture, clinico-epidemiological, and animal studies investigating MALAT1 in GBM.
- Analysis of MALAT1's regulatory mechanisms, including interactions with key signaling pathways (SOX2, WNT, ERK/MAPK) and microRNAs (miRNA-101, miR-203, miR-140, miR-155).
- Examination of MALAT1's impact on GBM cell properties such as stemness, apoptosis, autophagy, epithelial-mesenchymal transition, and drug resistance.
Main Results:
- Evidence suggests MALAT1 promotes GBM by enhancing stemness, inducing autophagy, suppressing apoptosis, increasing temozolomide resistance, and potentially increasing blood-brain barrier permeability.
- Conversely, some studies indicate MALAT1 suppresses GBM by inhibiting ERK/MAPK and MMP2 signaling and repressing miR-155.
- MALAT1's expression and function are context-dependent, leading to conflicting results regarding its role as a tumor promoter or suppressor.
Conclusions:
- MALAT1 is a significant, albeit complex, player in GBM pathogenesis, exhibiting both oncogenic and tumor-suppressive activities.
- Understanding the precise mechanisms and context-specific functions of MALAT1 is critical for developing effective GBM therapies.
- Further research utilizing diverse models, including primary GBM cultures and in vivo systems, is essential to elucidate MALAT1's definitive role.
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