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

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.