神經膠質母細胞瘤（GBM）等高級別膠質瘤是顱內常見腫瘤，致死率高，預後極差。近年來對膠質瘤的治療有所突破，但總的生存期僅能延長數月。一系列的促癌基因表達及功能異常和膠質瘤發生、發展密切相關。目前研究聚焦於探究新的關鍵信號通路和分子靶點。
曹聰課題組多年來研究證實G蛋白抑制性α亞單位1和3（Gαi1/3蛋白）是多個信號通路中的關鍵分子。在多個細胞及生長因子刺激下，Gαi1/3蛋白和受體酪氨酸激酶（RTKs）等受體結合，並介導下游信號（PI3K-Akt-mTOR及Erk-MAPK等）轉導（Science Advances 2022 [1], PNAS 2018 [2], Protein & Cell 2022a/b [3, 4]，Science Signaling， 2009 [5]，Oncogene 2018, 2021 [6, 7]，IJBS 2022 [8]，Theranostics 2018，2021a/b [9-11]等論文）。課題組前期研究發現膠質瘤患者腫瘤組織標本中Gαi1/3表達顯著上調；敲減、敲除Gαi1/3後可顯著抑制膠質瘤細胞體外及在小鼠顱內生長（Oncogene2018 [6]，Theranostics 2021a [9]）。但Gαi1/3蛋白表達調控的分子機制並不明確。YME1L（YME1 Like 1 ATPase）是AAA家族ATP酶的主要成員，位於線粒體內膜[12]。YME1L對維持線粒體的形態、功能和可塑性至關重要[13]。YME1L在線粒體內膜內組裝成同源寡聚物，參與降解線粒體蛋白：包括脂質轉運蛋白、線粒體內膜易位蛋白及OPA1等；YME1L缺失導致線粒體分裂增加，線粒體碎片化；YME1L還參與細胞增殖並抑制細胞凋亡 [13]。但YME1L在人類膠質瘤中的表達和潛在功能仍不清楚。
2022年10月19日，蘇州大學曹聰課題組在Protein & Cell在線發表了題為YME1L overexpression exerts pro-tumorigenic activity in glioma by promoting Gαi1 expression and Akt activation 的研究論文，該研究揭示了YME1L通過促進Gαi1蛋白表達和下游Akt活化促膠質瘤細胞生長。
結合TCGA數據庫和患者組織標本發現，YME1L在膠質瘤組織中表達顯著上調，且僅在線粒體中富集。在體外培養的人膠質瘤細胞中，運用病毒shRNA敲減或CRISPR/Cas9方法敲除YME1L顯著抑制細胞的生長、增殖和遷移，並誘導細胞線粒體損傷和細胞凋亡；而運用病毒載體過表達YME1L則促膠質瘤細胞生長。機制研究發現，膠質瘤細胞中敲減及敲除YME1L後，Gαi1表達下調，下游Akt抑制；而過表達YME1L後，Gαi1表達水平增加，Akt激活。
Gαi1過表達或導入持續活化的Akt（caAkt1）減輕YME1L敲除後抗膠質瘤細胞作用。在體研究發現，YME1L敲除後的人膠質瘤細胞在小鼠顱內生長顯著抑制；腫瘤組織內Gαi1表達下調，Akt活化抑制。綜上，YME1L通過介導Gαi1-Akt信號激活促膠質瘤細胞生長，該通路或是膠質瘤的一個重要新的治療靶點。
原文鏈接：https://doi.org/10.1093/procel/pwac011
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