Knockdown of OCT4 suppresses the growth and invasion of pancreatic cancer cells through inhibition of the AKT pathway

Abstract

Octamer-binding transcription factor 4 (OCT4) is one of the factors associated with self-renewal and differentiation in cancer stem cells, and is crucial for the progression of various types of human malignancy. However, the expression and function of OCT4 in human pancreatic cancer has not been fully elucidated. The purpose of the present study was to investigate the function and molecular mechanisms of OCT4 in pancreatic cancer cells. The clinical significance of OCT4 expression was assessed by an immunohistochemical assay using a tissue microarray procedure in pancreatic cancer tissues and cells with different degrees of differentiation. A loss-of-function approach was used to examine the effects of a lentivirus-mediated OCT4 small hairpin RNA vector on biological behaviors, including cell proliferative activity and invasive potential. The results demonstrated that the expression levels of OCT4 protein in cancer tissues were significantly elevated compared with those in adjacent non-cancerous tissues (65.0 vs. 42.5%; P=0.005), which was correlated with tumor differentiation (P=0.008). The knockdown of OCT4 inhibited the proliferation and invasion of pancreatic cancer cells (Panc-1) expressing high levels of OCT4, accompanied with decreased expression of AKT, proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-2 (MMP-2). In conclusion, the present study reveals that the increased expression of OCT4 is correlated with the differentiation of pancreatic cancer, while knockdown of OCT4 suppresses the growth and invasion of pancreatic cancer cells through inhibition of AKT pathway-mediated PCNA and MMP-2 expression, suggesting that OCT4 might serve as a potential therapeutic target for the treatment of pancreatic cancer.

eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth

“…Our discovery that eIF5A-PEAK1 couples to YAP1/TAZ signaling provides a plausible mechanism for how PEAK1, a focal adhesion and cytoskeleton-associated kinase, can communicate with the nucleus to control cancer cell proliferation and differentiation. Understanding how this signaling pathway is regulated has clinical relevance as eIF5A, PEAK1, YAP1/TAZ and their downstream STFs have all been shown to be amplified in PDAC patient tissues (16, 18–20, 23, 24, 28, 37, 39, 40). …”

Dual inhibiting OCT4 and AKT potently suppresses the propagation of human cancer cells

“…These results indicate a reciprocal negative regulation between AKT and OCT4. However, on the other hand, PI3K-AKT-activated disassociation of a transcription repressor from the OCT4 promoter was considered to account for valproic acid-induced up-regulation of OCT4 expression in mouse myoblast C2C12 cells and mouse embryonic carcinoma P19 cells33, and knocking-down OCT4 in pancreatic cancer cells decreased the mRNA and protein levels of total AKT34, implicating a positive correlation between AKT and OCT4. Such apparent discrepancy may be explained by the fact that either AKT or OCT4 controls numerous downstream targets that may indirectly regulate its counterpart in different modes at multiple levels (e.g., transcriptional, post-transcriptional, and/or post-translational level)13.…”

Markers of pancreatic cancer stem cells and their clinical and therapeutic implications

“…Oct4, combining with other factors such as SOX2 and NANOG, participates not only in the regulation of gene expression responsible for cell renewal and differentiation but also affects the expression of other factors such as fibroblast growth factor 4 (FGF4) [122,123]. Statistically significant increased expression of Oct4 can be found in metaplastic ducts (79.2%) compared to malignant (19.4%) and nonmalignant (16.7%) tissue and high Oct4 expression is correlated with tumor differentiation [124,125]. In order to explain the role of Oct4 in pancreatic tumors, Lu et al knocked down both Oct4 and Nanog, which contributed to a reduction in proliferation, migration and invasion of PC stem cells and to increased sensitivity to chemotherapy with gemcitabine.…”