基于对肿瘤干细胞外泌体LAMB1的调节研究胰腺癌化疗耐药机制

Pancreatic cancer chemotherapy drug resistance is one of the important factors affecting the effect of chemotherapy, we found the change of tissue microenvironment is one of the important reasons affecting the chemotherapy sensitivity. The study found that the exosome LAMB1 from cancer stem cells play an important role in regulating tissue microenvironment. Previous studies have found that LAMB1 can promote pancreatic cancer EMT by regulation PI3K/Akt and MEK/ERK signal. Therefore, looking for new regulation molecules for LAMB1 expression will be more beneficial to the clinical treatment of pancreatic cancer. Through the study of the gene chip from pancreatic cancer patients serum exosome and big data analysis found that the miRNA Let-7a-3p can inhibition the expression of LAMB1 by targeted for 3 'UTR region of LAMB1 after transcription, which is verified by experiment. In order to further verify the reversal effect and to elucidate the role of specific mechanism of Let-7a-3p to LAMB1 mediated EMT and pancreatic cancer chemotherapy drug resistance. This project from clinical, cellular and animal experiments to explore: The effective mechanism of cancer stem cells to EMT and chemotherapy drug in pancreatic cancer by regulation microenvironmental. Hopefully, our study will providing a new theoretical basis and therapeutic targets for the clinical treatment of pancreatic cancer.

胰腺癌化疗耐药是影响其化疗效果的重要因素，其中组织微环境的改变是重要原因，而肿瘤干细胞来源的外泌体LAMB1在微环境调节中起重要作用。前期研究发现，外泌体LAMB1可通过PI3K/Akt和MEK/ERK信号通路促进胰腺癌上皮-间质化转移(EMT)，进而影响化疗耐药。因此，寻找可靶向LAMB1的分子将更有利于胰腺癌的临床治疗。前期通过基因芯片筛查及大数据分析发现，miRNA Let-7a-3p可靶向作用于LAMB1的3'UTR区，对其进行转录后抑制，并得到实验证实。为了进一步验证Let-7a-3p靶向肿瘤干细胞LAMB1对胰腺癌化疗耐药的调控作用，并阐明其具体作用机制，本项目拟从临床、细胞、动物实验方面探讨：肿瘤干细胞通过微环境调控胰腺癌EMT及化疗耐药的作用机制，旨在为胰腺癌的临床治疗提供新的理论基础和治疗靶点。

胰腺癌是(PC)最常见的致命恶性肿瘤之一，由于频繁复发和缺乏有效的治疗，总体5年生存率低于5%。手术切除和化疗被认为是治疗PC的主要方法。目前，基于吉西他滨的化疗是PC的一线治疗。然而，化疗耐药严重阻碍了PC的治疗。长链非编码rna (lncRNAs)和microRNAs (miRNAs)的异常调节，介导胰腺癌化疗耐药和转移是导致胰腺癌预后不良的关键原因。LncRNA生长抑制特异5 (GAS5)被报道为多种癌症的肿瘤抑制因子。然而，GAS5及其相关miRNAs在PC中的功能尚不清楚。本研究探讨了GAS5在PC吉西他滨耐药和转移中的潜在作用和机制。结果表明：GAS5的过表达通过直接结合和抑制miR-221的表达，增强SOCS3的表达，从而抑制PC细胞的增殖、迁移、吉西他滨耐药、干细胞样特性和上皮间质转化(EMT)。而PC细胞中SOCS3过表达逆转了miR-221的上述影响。因此，lncRNA GAS5作为miR-221的竞争内源性RNA，通过调控miR-221/SOCS3通路介导EMT和肿瘤干细胞的自我更新，抑制PC中的细胞生长、转移和吉西他滨耐药。该部分已发表SCI论文Mol Ther Nucleic Acids. 2018; 13: 472 - 482. (IF,7.032 )。.除了胰腺癌外，我们还研究了肿瘤微环境和膀胱癌(BC)的关系。环状RNA VANGL1 (circVANGL1)通过海绵吸收某些microrna (miRNAs)作为肿瘤启动子。然而，circVANGL1在膀胱癌中的作用仍不清楚。本研究证实了circVANGL1、miRNA和相关蛋白之间的相互关系，circVANGL1在BC组织和细胞系中均上调，沉默circVANGL1的表达可以抑制细胞的侵袭、迁移和增殖，circVANGL1通过海绵细胞miR-1184上调miR-1184靶基因胰岛素样生长因子结合蛋白2 (IGFBP2)的表达，从而促进了BC的侵袭性生物学行为。结果表明，circVANGL1通过新的circVANGL1/miR-1184/IGFBP2轴作为肿瘤启动子。希望我们的研究能为BC的临床治疗提供新的思路。该部分已发表SCI论文Cancer Med. 2020; 9(2):700-710. (IF,3.491)。