Abstract
BackgroundIntegrin alpha 2 (ITGA2) has been recently reported to be an oncogene and to play crucial roles in tumor cell proliferation, invasion, metastasis, and angiogenesis. Our previous study showed that ITGA2 was overexpressed in pancreatic cancer and promoted its progression. However, the mechanism of ITGA2 overexpression and other mechanisms for promoting the progression of pancreatic cancer are still unclear.MethodsThe GEPIA database was used to confirm the expression of ITGA2 in pancreatic cancer. To verify the influence of ITGA2 and TGF-β on the morphological changes of pancreatic cancer and tumor cell progression, we conduct CCK8 test, plate cloning, flow cytometry experiments and animal experiments. Then we conduct Western blot, RT-qPCR to explore the relationship between ITGA2 and TGF-β, and then find the key molecules which can regulate them by immunoprecipitation, Western blot, RT-qPCR, CHIP, nuclear and cytoplasmic separation test.ResultsThe results of the present study show that the abnormal activation of KRAS induced the overexpression of ITGA2 in pancreatic cancer. Moreover, ITGA2 expression significantly suppressed the activation of the TGF-β pathway. ITGA2 silencing enhanced the anti-pancreatic cancer proliferation and tumor growth effects of TGF-β. Mechanistically, ITGA2 expression suppressed the activation of the TGF-β pathway by inhibiting the SMAD2 expression transcriptionally. In addition, it interacted with and inhibited the nuclear translocation of TFCP2, which induced the SMAD2 expression as a transcription factor. Furthermore, TFCP2 also induced ITGA2 expression as a transcription factor, and the TFCP2 feedback regulated the ITGA2-TFCP2-SMAD2 pathway.ConclusionsTaken together, these results indicated that ITGA2 expression could inhibit the activation of the TGF-β signaling pathway in pancreatic cancer via the TFCP2-SMAD2 axis. Therefore, ITGA2, by effectively enhancing the anti-cancer effects of TGF- β, might be a potential clinical therapeutic target for pancreatic cancer.
Highlights
Integrin alpha 2 (ITGA2) has been recently reported to be an oncogene and to play crucial roles in tumor cell proliferation, invasion, metastasis, and angiogenesis
Abnormal KRAS activation induced the overexpression of ITGA2 in pancreatic cancer cells The KRAS-mediated RAS signaling pathway plays an important role in the occurrence and development of diseases and resistance to the chemotherapeutic drug
Yao et al found that the oncogenic KRAS mutations upregulated the ITGA2 protein on the cell surface [16] (Fig. 1a)
Summary
Integrin alpha 2 (ITGA2) has been recently reported to be an oncogene and to play crucial roles in tumor cell proliferation, invasion, metastasis, and angiogenesis. Our previous study showed that ITGA2 was overexpressed in pancreatic cancer and promoted its progression. Integrin α2 and β1 subunits form heterodimers of the transmembrane receptors, which are important molecules involved in tumor cell proliferation, migration, survival, and angiogenesis [5, 6]. ITGA2 is overexpressed in many cancers such as hepatocellular carcinoma [8], ovarian cancer [9], and pancreatic ductal adenocarcinoma [10], and is thought to be related to cell adhesion and cell surface-mediated signal transduction. Our previous studies showed that overexpressed ITGA2 can upregulate PD-L1 to activate the STAT3 signaling pathway and thereby promote tumor cell progression [10], the carcinogenic mechanism of ITGA2 in pancreatic cancer still needs elucidation in further research
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
