Makker Annu, Goel Madhu Mati, Mahdi Abbas Ali, Bhatia Vikram, Das Vinita, Agarwal Anjoo, Pandey Amita
Post-Graduate Department of Pathology, King George's Medical University, Lucknow, India.
Department of Biochemistry, King George's Medical University, Lucknow, India.
Indian J Med Res. 2016 May;143(Supplement):S112-S119. doi: 10.4103/0971-5916.191808.
BACKGROUND & OBJECTIVES: Despite their high occurrence and associated significant level of morbidity manifesting as spectrum of clinical symptoms, the pathogenesis of uterine leiomyomas (ULs) remains unclear. We investigated expression profile of tumour suppressor genes PTEN (phosphatase and tensin homolog deleted on chromosome ten) and LKB1 (liver kinase B1), and key signaling components of P13K (phosphatidylinositol 3-kinase)/Akt (protein kinase B)/mTOR (mammalian target of rapamycin) pathway in leiomyomas and adjacent normal myometrium in women of reproductive age, to explore the possibility of targeting this pathway for future therapeutic implications.
Real time PCR (qPCR) was used to quantify relative gene expression levels of PTEN, Akt1, Akt2, mTOR, LKB1 and VEGFA (vascular endothelial growth factor A) in leiomyoma as compared to adjacent normal myometrium. Immunohistochemistry was subsequently performed to analyze expression of PTEN, phospho-Akt, phospho-mTOR, phospho-S6, LKB1 and VEGFA in leiomyoma and adjacent normal myometrium.
Significant upregulation of PTEN (2.52 fold; P=0.03) and LKB1 (3.93 fold; P0.01), and downregulation of VEGFA (2.95 fold; P=0.01) genes were observed in leiomyoma as compared to normal myometrium. Transcript levels of Akt1, Akt2 and mTOR did not vary significantly between leiomyoma and myometrium. An increased immunoexpression of PTEN (P=0.015) and LKB1 (P<0.001) and decreased expression of VEGFA (P=0.01) was observed in leiomyoma as compared to myometrium. Immunostaining for activated (phosphorylated) Akt, mTOR and S6 was absent or low in majority of leiomyoma and myometrium.
INTERPRETATION & CONCLUSIONS: Upregulation of PTEN and LKB1 in concert with negative or low levels of activated Akt, mTOR and S6 indicates that PI3K/Akt/mTOR pathway may not play a significant role in pathogenesis of leiomyoma.
尽管子宫平滑肌瘤（ULs）发病率高且伴有一系列临床症状导致显著的发病水平，但其发病机制仍不清楚。我们研究了育龄期女性子宫平滑肌瘤及邻近正常肌层中肿瘤抑制基因PTEN（第10号染色体缺失的磷酸酶和张力蛋白同源物）和LKB1（肝脏激酶B1）的表达谱，以及PI3K（磷脂酰肌醇3激酶）/Akt（蛋白激酶B）/mTOR（雷帕霉素哺乳动物靶蛋白）通路的关键信号成分，以探索针对该通路进行未来治疗的可能性。
采用实时定量聚合酶链反应（qPCR）定量子宫平滑肌瘤与邻近正常肌层中PTEN、Akt1、Akt2、mTOR、LKB1和VEGFA（血管内皮生长因子A）的相对基因表达水平。随后进行免疫组织化学分析子宫平滑肌瘤及邻近正常肌层中PTEN、磷酸化Akt、磷酸化mTOR、磷酸化S6、LKB1和VEGFA的表达。
与正常肌层相比，子宫平滑肌瘤中PTEN基因显著上调（2.52倍；P=0.03），LKB1基因显著上调（3.93倍；P<0.01），VEGFA基因下调（2.95倍；P=0.01）。子宫平滑肌瘤与肌层之间Akt1、Akt2和mTOR的转录水平无显著差异。与肌层相比，子宫平滑肌瘤中PTEN（P=0.015）和LKB1（P<0.001）的免疫表达增加，VEGFA的表达降低（P=0.01）。在大多数子宫平滑肌瘤和肌层中，活化（磷酸化）Akt、mTOR和S6的免疫染色缺失或较弱。
PTEN和LKB1的上调以及活化的Akt、mTOR和S6呈阴性或低水平表明PI3K/Akt/mTOR通路可能在子宫平滑肌瘤的发病机制中不起重要作用。
