将 CERS6-AS1/FGFR1 轴作为限制基质细胞的合成脆弱性，以支持套细胞淋巴瘤的增殖。
Targeting CERS6-AS1/FGFR1 axis as synthetic vulnerability to constrain stromal cells supported proliferation in Mantle cell lymphoma.
发表日期：2024 Jul 13
作者：
Udita Jindal, Mukesh Mamgain, Uttam Kumar Nath, Isha Sharma, Bhaskar Pant, Ankita Sharma, Archita Gupta, Khaliqur Rahman, Sunil Yadav, Manish Pratap Singh, Shaktiprasad Mishra, Chandra Praksah Chaturvedi, Jose Courty, Navin Singh, Seema Gupta, Sanjeev Kumar, Shailendra Prasad Verma, Saumyaranjan Mallick, Ajay Gogia, Sunil Raghav, Jayanta Sarkar, Kinshuk Raj Srivastava, Dipak Datta, Neeraj Jain
来源：
Stem Cell Research & Therapy
摘要：
肿瘤微环境中基质细胞和肿瘤细胞之间的相互作用是套细胞淋巴瘤（MCL）进展和治疗耐药的关键因素。我们发现了一种长非编码 RNA CERS6-AS1，它在 MCL 中表达上调，并且与较差的总体生存率相关。 CERS6-AS1 表达在基质微环境内的原发性 MCL 和粘附于基质层的 MCL 细胞子集中升高。这些基质粘附的 MCL 亚群比悬浮的对应物表现出癌症干细胞特征。从机制上讲，我们发现下调 MCL 中的 CERS6-AS1 会降低成纤维细胞生长因子受体-1 (FGFR1) 的表达，其表达归因于其与 RNA 结合蛋白核仁素相互作用的丧失。此外，通过计算机模拟方法，我们发现核仁素与 FGFR1 的 5'UTR 之间存在直接相互作用，从而调节 FGFR1 转录本的稳定性。我们发现 CERS6-AS1 与癌症干细胞特征和 Wnt 信号传导呈正相关。在此基础上，我们探索了潜在的治疗策略，将核仁素靶向剂与 FGFR1 抑制相结合，显着有助于逆转癌症干细胞特征并消除基质层上的原代 MCL 细胞生长。这些发现提供了对肿瘤细胞与基质细胞相互作用之间涉及 CERS6-AS1、核仁素和 FGFR1 轴相关串扰的调控网络的机制见解，并强调了针对 MCL 中非编码 RNA 的治疗潜力。© 2024。 ，获得施普林格自然有限公司的独家许可。
The interaction between stromal and tumor cells in tumor microenvironment is a crucial factor in Mantle cell lymphoma (MCL) progression and therapy resistance. We have identified a long non-coding RNA, CERS6-AS1, upregulated in MCL and associated with poor overall survival. CERS6-AS1 expression was elevated in primary MCL within stromal microenvironment and in a subset of MCL cells adhered to stromal layer. These stromal-adhered MCL-subsets exhibited cancer stem cell signatures than suspension counterparts. Mechanistically, we found that downregulating CERS6-AS1 in MCL reduced Fibroblast Growth Factor Receptor-1 (FGFR1), expression attributed to loss of its interaction with RNA-binding protein nucleolin. In addition, using in-silico approach, we have discovered a direct interaction between nucleolin and 5'UTR of FGFR1, thereby regulating FGFR1 transcript stability. We discovered a positive association of CERS6-AS1 with cancer stem cell signatures, and Wnt signaling. Building on these, we explored potential therapeutic strategies where combining nucleolin-targeting agent with FGFR1 inhibition significantly contributed to reversing cancer stem cell signatures and abrogated primary MCL cell growth on stromal layer. These findings provide mechanistic insights into regulatory network involving CERS6-AS1, nucleolin, and FGFR1 axis-associated crosstalk between tumor cells and stromal cell interaction and highlights therapeutic potential of targeting a non-coding RNA in MCL.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.