HIF-3α Facilitates the Proliferation and Migration in Pancreatic Cancer by Inhibiting Autophagy Through Downregulating TP53INP2.

Pancreatic cancer is a highly aggressive malignant tumor, often diagnosed late, leading to a poor prognosis and extremely high mortality rates. In recent years, the role of cellular autophagy in tumors has become increasingly prominent, gradually becoming an important target for malignant tumors. HIF-3α is a member of HIF family with potential oncogenic function. However, the role of HIF-3α in pancreatic cancer is not clear. The present study revealed its role in pancreatic cancer by exploring the regulatory mechanism of HIF-3α on autophagy. HIF-3α was found markedly upregulated in pancreatic cancer cell lines. In HIF-3α silenced MiaPaCa-2 cells, largely declined migration distance, reduced number of invaded cells and colonies, increased number of autophagosome, downregulated p62, and upregulated Beclin1, LC3II/I, and ATG7 were observed, accompanied by elevated TP53INP2 expressions. on the contrary, in HIF-3α overexpressed PANC-1 cells, notably increased migration distance, and elevated number of invaded cells and colonies were observed, along with decreased autophagosome, upregulated p62, and downregulated Beclin1, LC3II/I, ATG7, and TP53INP2. Subsequently, HIF-3α overexpressed PANC-1 cells were transfected with TP53INP2 overexpressing vector. The influence of HIF-3α overexpression on the proliferation, migration, invasion, and autophagy was abolished by TP53INP2 overexpressing. Furthermore, HIF-3α overexpression facilitated the in vivo growth of PANC-1 cells, accompanied by the autophagy inhibition in tumor tissues, which were remarkably abolished by TP53INP2 overexpressing. Collectively, HIF-3α facilitated the proliferation and migration in pancreatic cancer by inhibiting autophagy through downregulating TP53INP2.