Sradhanjali Swatishree, Rout Padmalochan, Tripathy Devjyoti, Kaliki Swathi, Rath Suryasnata, Modak Rahul, Mittal Ruchi, Chowdary Tirumala Kumar, Reddy Mamatha M
The Operation Eyesight Universal Institute for Eye Cancer, LV Prasad Eye Institute, Bhubaneswar 751024, Odisha, India.
School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, Odisha, India.
Cancers (Basel). 2021 Oct 19;13(20):5248. doi: 10.3390/cancers13205248.
Retinoblastoma is usually initiated by biallelic gene inactivation. In addition, copy number alterations also contribute to RB pathogenesis. However, expression, its role in disease progression and correlation with RB histological risk factors are not well understood. We studied the expression of in enucleated RB patient specimens by immunohistochemistry. is overexpressed in RB compared to control retina. Our microarray gene expression analysis followed by qRT-PCR validation revealed that genes involved in glucose metabolism and migration are significantly downregulated in knockdown cells. Further, targeting in RB cells using small molecule compounds or shRNAs led to decreased cell survival and migration, increased apoptosis and cell cycle arrest, suggesting that inhibition can be a potential therapeutic strategy. We also noted that inhibition results in reduction in glucose uptake, lactate production, ROS levels and gelatinolytic activity of active-MMP9, explaining a possible mechanism of in RB. Taking clues from our findings, we tested a combination treatment of RB cells with carboplatin and inhibitors to find enhanced therapeutic efficacy compared to single drug treatment. Thus, inhibition can be a potential therapeutic strategy in combination with existing chemotherapy drugs to restrict tumor cell growth in RB.
视网膜母细胞瘤通常由双等位基因失活引发。此外，拷贝数改变也促成了视网膜母细胞瘤的发病机制。然而，其表达、在疾病进展中的作用以及与视网膜母细胞瘤组织学危险因素的相关性尚未得到充分了解。我们通过免疫组织化学研究了摘除眼球的视网膜母细胞瘤患者标本中的表达情况。与对照视网膜相比，视网膜母细胞瘤中表达上调。我们的微阵列基因表达分析随后进行qRT-PCR验证，结果显示参与葡萄糖代谢和迁移的基因在敲低细胞中显著下调。此外，使用小分子化合物或短发夹RNA靶向视网膜母细胞瘤细胞中的，会导致细胞存活率和迁移率降低，凋亡增加以及细胞周期停滞，这表明抑制可能是一种潜在的治疗策略。我们还注意到，抑制会导致葡萄糖摄取、乳酸生成、活性氧水平以及活性基质金属蛋白酶9的明胶酶解活性降低，这解释了在视网膜母细胞瘤中的一种可能机制。根据我们的研究结果，我们测试了用卡铂和抑制剂联合治疗视网膜母细胞瘤细胞，以发现与单药治疗相比具有更高的治疗效果。因此，抑制与现有化疗药物联合使用可能是一种潜在的治疗策略，以限制视网膜母细胞瘤中的肿瘤细胞生长。
