IGF-1R signaling controls various vital cellular functions and this signaling is deregulated in many cancers, including pancreatic cancer. Several efforts have mainly focused on inhibiting the IGF-1R signaling cascade. The outcomes of these focused preclinical studies have been positive, whereas clinical trials of IGF-1R inhibitors in pancreatic cancer have failed, raising the questions about this therapeutic approach. This necessitates a better understanding of the role of IGF-1R signaling in pancreatic cancer. We investigated the impact of IGF-1R signaling on crucial transcription factors and identified the FOXC1 as one of the crucial regulator of IGF-1R signaling. We employed genetic approaches to overexpress and silence FOXC1 in pancreatic cancer cells. Our results demonstrate that IGF-1R and FOXC1 seem to positively regulate each other. Further, FOXC1 increased the metastatic abilities of pancreatic cancer cells by enhancing cell proliferation, migration, invasion, epithelial-to-mesenchymal transition, and angiogenesis. The data from xenograft experiments further established the importance of FOXC1 in pancreatic tumorigenesis. In conclusion, FOXC1 is a potent oncogenic transcription factor, which promotes pancreatic cancer growth and metastasis. Thus, targeting FOXC1 could be a potential therapeutic strategy against pancreatic cancer.

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BACKGROUD: Pancreatic cancer is one of the most aggressive cancers due to ineffective treatment options and its high metastatic abilities. This highlights the significance for the development of effective modalities to treat this deadly disease. Dysregulation of IGF-1R signaling has been shown to be involved in the invasive and metastatic potential of several cancer types. Currently, the mechanism by which IGF-1R promotes pancreatic cancer is not well understood. Our preliminary transcription factor profiling array indicated that FOXC1 was regulated by IGF-1R. Therefore, in the present study, we investigated the role of FOXC1 in pancreatic carcinogenesis. METHODS: Western blot and qRT-PCR analysis were done to measure the expression levels of FOXC1 in a panel of pancreatic cancer cell lines along with normal pancreatic cells. IHC analysis of the levels of FOXC1 by tumor stage in human pancreatic ductal adenocarcinoma tissues and normal pancreas tissue was performed using tissue microarray. Immunofluorescence analysis was performed to compare the expression levels of FOXC1 in normal and pancreatic cancer cells. To investigate the role of FOXC1 on pancreatic cancer cell growth and metastasis, we used an RNA interference approach to silence FOXC1 in HPAC pancreatic cancer cells. MTS assay was performed to study the cell viability. Metastatic capabilities of FOXC1 silenced HPAC cells were examined using matrigel invasion, scratch assay, and soft agar colony forming assays. To further confirm, Western blotting analysis was done to evaluate the key intermediates involved in proliferation, epithelial mesenchymal transition, and apoptosis. Exogenous expression of FOXC1 in MIAPaCa-2 cells was also used to understand the oncogenic role of FOXC1 in pancreatic cancer. To further validate, xenograft studies with FOXC1 silenced HPAC cells were performed. RESULTS: Expression of FOXC1 was upregulated in pancreatic cancer cell lines. Silencing FOXC1 in HPAC cells drastically decreased the cell viability; however, it did not alter the viability of normal pancreatic cells. Furthermore, it also significantly reduced the invasive, migratory, and colony forming abilities of pancreatic cancer cells. Targeting FOXC1 significantly altered the key signaling molecules involved in proliferation, EMT, and apoptosis of HPAC cells. Exogenous overexpression of FOXC1 in MIAPaCa-2 cells also validated the oncogenic role of FOXC1. HPAC xenograft models further demonstrated the therapeutic role of FOXC1 in pancreatic cancer. CONCLUSION: To conclude, our results suggest that silencing FOXC1 effectively targets pancreatic cancer cells suggesting that it could be a potential novel therapeutic option. Citation Format: Ramadevi Subramani, Fernando A. Camacho, Carly Levin, Joshua Medel, Sai Navana Kolli, Sushmita Bose Nandy, Diego A. Pedroza, Rajkumar Lakshmanaswamy. FOXC1 promotes pancreatic cancer cell proliferation and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3517. doi:10.1158/1538-7445.AM2017-3517