Purpose Musashi 2 (MSI2) is reported to be a potential oncoprotein in cases of leukemia and several solid tumors. However, its expression, function, and regulation in pancreatic ductal adenocarcinoma (PDAC) cases have yet to be demonstrated. Therefore, in the present study, we investigated the clinical significance and biologic effects of MSI2 expression in PDAC cases and sought to delineate the clinical significance of the newly identified Krüppel-like factor 4 (KLF4)/MSI2 regulatory pathway. Experimental Design MSI2 expression and its association with multiple clinicopathologic characteristics in human PDAC specimens were analyzed immunohistochemically. The biologic functions of MSI2 regarding PDAC cell growth, migration, invasion, and metastasis were studied using gain-and loss-of-function assays both in vitro and in vivo. Regulation of MSI2 expression by KLF4 was examined in several cancer cell lines, and the underlying mechanisms were studied using molecular biologic methods. Results MSI2 expression was markedly increased in both PDAC cell lines and human PDAC specimens, and high MSI2 expression was associated with poor prognosis for PDAC. Forced MSI2 expression promoted PDAC proliferation, migration, and invasion in vitro and growth and metastasis in vivo, whereas knockdown of MSI2 expression did the opposite. Transcriptional inhibition of MSI2 expression by KLF4 occurred in multiple PDAC cell lines as well as mouse models of PDAC. Conclusions Lost expression of KLF4, a transcriptional repressor of MSI2, results in overexpression of MSI2 in PDACs, which may be a biomarker for accurate prognosis. A dysregulated KLF4/MSI2 signaling pathway promotes PDAC progression and metastasis.

The hepatitis B virus (HBV)-X protein (HBx) induces malignant transformation of liver cells, and elevated expression of alpha-fetoprotein (AFP) is a significant biomarker of hepatocarcinogenesis. However, the role of AFP in HBV-related hepatocarcinogenesis is unclear. In this study, we investigated the regulatory impact of AFP expression on HBx-mediated malignant transformation of human hepatocytes. We found that HBV induced the expression of AFP before that of oncogenes, e.g., Src, Ras and chemokine (C-X-C motif) receptor 4 (CXCR4), and AFP activated protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in HBV-related HCC tissues and in human liver cells transfected with HBx. Cytoplasmic AFP interacted with and inhibited phosphatase and tensin homolog deleted on chromosome 10 (PTEN), activating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway and promoting mTOR-mediated stimulation of the transcription factor hypoxia inducible factor-1α (HIF-1α), and therefore led to the activation of the promoters of Src, CXCR4, and Ras genes. On the contrary, reduced expression of AFP by siRNA resulted in the repression of p-mTOR, pAKT, Src, CXCR4, and Ras in human malignant liver cells. Taken together, for the first time our study indicates that HBx-induced AFP expression critically promote malignant transformation in liver cells through the activation of PI3K/mTOR signaling.

Gastrointestinal (GI) cancer is characterized by its aggressiveness, but the underlying mechanism is not fully understood. Studies reveal that epithelial to mesenchymal transition (EMT), which is regulated by a series of transcription factors and signaling pathways, is strongly associated with GI cancer cell proliferation, invasion and metastasis. In essential, EMT is a product of crosstalk between signaling pathways. Krüppel-like factor 4 (KLF4), a zinc finger-type transcription factor, is decreased or lost in most GI cancers. By transcriptional regulating its downstream target genes, KLF4 plays important roles of GI cancer tumorigenesis, proliferation and differentiation. In this review, we focus on the mechanism of KLF4 in GI cancer EMT, and demonstrate that through crosstalk with TGF-β, Notch, and Wnt signaling pathways, KLF4 negatively regulates EMT of GI cancers. Finally, we indicate the challenging new frontiers for KLF4 which contributes to better understanding of the mechanism of GI cancer aggressiveness.

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