FOSL1通过调节细胞干性、转移和多药外排系统驱动胰腺癌细胞的恶性进展。

FOSL1 drives the malignant progression of pancreatic cancer cells by regulating cell stemness, metastasis and multidrug efflux system.

作者信息

Liu Xiaolong, Zhang Xueyan, Zeng Tingyu, Chen Yali, Ye Liu, Wang Shuping, Li Yulan

机构信息

The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, PR China.

Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, PR China.

出版信息

J Transl Med. 2025 Mar 4;23(1):268. doi: 10.1186/s12967-025-06304-w.

DOI:10.1186/s12967-025-06304-w

PMID:40038751

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11877717/

Abstract

BACKGROUND

Targeted therapy is an effective strategy for the treatment of advanced and metastatic pancreatic cancer, one of the leading causes for cancer-related death worldwide. To address the limitations of existing targeted drugs, there is an urgently need to find novel targets and therapeutic strategies. Transcription factor FOS like 1 (FOSL1) is a potential therapeutic target for challenging pancreatic cancer, which contributes to the malignant progression and poor gnosis of pancreatic cancer. High mobility group A1 (HMGA1) is a nonhistone chromatin structural protein that contributes to malignant progression and poor prognosis of cancer.

METHODS

Human FOSL1 complete RNA, shRNA against FOSL1 and shRNA against HMGA1 lentiviral recombination vectors were used to overexpress FOSL1 and knock down FOSL1 and HMGA1. RNA sequencing, Q-PCR and Western blots were used to investigate the mechanism of FOSL1 in regulating the proliferation of pancreatic cancer cells. The relationship between FOSL1 and HMGA1 were analyzed by co-immunoprecipitation Mass spectrometry, Q-PCR of chromatin immunoprecipitation and Western blots. The regulation of FOSL1 and HMGA1 in the invasion and migration, stemness, and multidrug efflux system were determined by transwell assay, sphere formation assay, immunofluorescence, Q-PCR and Western blots.

RESULTS

We found that FOSL1 promoted the proliferation and progression of pancreatic cancer by trigging stemness, invasion and metastasis, and drug resistance. HMGA1 was a key downstream target regulated by FOSL1 at the transcriptional level and directly interacted with FOSL1. Knockdown of HMGA1 inhibited the proliferation of pancreatic cancer cells by regulating the expression of genes related to stemness, epithelial-mesenchymal transition and multidrug efflux system. Targeted inhibition of FOSL1 and HMGA1 expression significantly inhibited the proliferation of pancreatic cancer cells.

CONCLUSION

FOSL1 promote the malignant progression of pancreatic cancer by promoting HMGA1 expression. Targeting FOSL1 and HMGA1 in monotherapy or combination therapy is a promising strategy for the treatment of advanced and metastasis pancreatic cancer.

摘要

背景

靶向治疗是治疗晚期和转移性胰腺癌的有效策略，胰腺癌是全球癌症相关死亡的主要原因之一。为解决现有靶向药物的局限性，迫切需要寻找新的靶点和治疗策略。转录因子FOS样蛋白1（FOSL1）是挑战性胰腺癌的潜在治疗靶点，它促进胰腺癌的恶性进展和不良预后。高迁移率族蛋白A1（HMGA1）是一种非组蛋白染色质结构蛋白，它促进癌症的恶性进展和不良预后。

方法

使用人FOSL1全长RNA、针对FOSL1的短发夹RNA（shRNA）和针对HMGA1的shRNA慢病毒重组载体来过表达FOSL1以及敲低FOSL1和HMGA1。采用RNA测序、定量聚合酶链反应（Q-PCR）和蛋白质免疫印迹法研究FOSL1调节胰腺癌细胞增殖的机制。通过免疫共沉淀质谱分析、染色质免疫沉淀Q-PCR和蛋白质免疫印迹法分析FOSL1与HMGA1之间的关系。通过Transwell实验、成球实验、免疫荧光、Q-PCR和蛋白质免疫印迹法确定FOSL1和HMGA1在侵袭、迁移、干性和多药外排系统中的调节作用。

结果

我们发现FOSL1通过触发干性、侵袭、转移和耐药性促进胰腺癌的增殖和进展。HMGA1是FOSL1在转录水平调控的关键下游靶点，且直接与FOSL1相互作用。敲低HMGA1通过调节与干性、上皮-间质转化和多药外排系统相关基因的表达来抑制胰腺癌细胞的增殖。靶向抑制FOSL1和HMGA1的表达显著抑制胰腺癌细胞的增殖。