Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features

Abstract

Background & Aims Over-expression of FoxM1 correlates with poor prognosis in hepatocellular carcinoma (HCC). Moreover, the Ras-signaling pathway is found to be ubiquitously activated in HCC through epigenetic silencing of the Ras-regulators. We investigated the roles of FoxM1 in Ras-driven HCC, and on HCC cells with stem-like features. Methods We employed a transgenic mouse model that expresses the oncogenic Ras in the liver. That strain was crossed with a strain that harbor floxed alleles of FoxM1 and the MxCre gene that allows conditional deletion of FoxM1. FoxM1 alleles were deleted after development of HCC, and the effects on the tumors were analyzed. Also, FoxM1-siRNA was used in human HCC cell lines to determine its role in the survival of the HCC cells with stem cell features. Results Ras-driven tumors over-express FoxM1. Deletion of FoxM1 inhibits HCC progression. There was increased accumulation of reactive oxygen species (ROS) in the FoxM1-deleted HCC cells. Moreover, FoxM1-deletion caused a disproportionate loss of the CD44+ and EpCAM+ HCC cells in the tumors. We show that FoxM1 directly activates expression of CD44 in human HCC cells. Moreover, the human HCC cells with stem cell features are addicted to FoxM1 for ROS-regulation and survival. Conclusion Our results provide genetic evidence for an essential role of FoxM1 in the progression of Ras-driven HCC. In addition, FoxM1 is required for the expression of CD44 in HCC cells. Moreover, FoxM1 plays a critical role in the survival of the HCC cells with stem cell features by regulating ROS.

Plk1 Regulates the Repressor Function of FoxM1b by inhibiting its Interaction with the Retinoblastoma Protein

“…Its over-expression coincides with high-grade progression in almost all types of cancers, including those in breast12, liver34, lung56, prostate78, pancreas910, ovary11, brain12, nasopharynx13, esophagus14, and also in certain leukemia15. Moreover, a study that analyzed 18,000 human tumors with outcomes for 39 different malignancies identified over-expression of FoxM1 as a major predictor for poor prognosis16.…”

Immunotherapy based on dendritic cells pulsed with CTPFoxM1 fusion protein protects against the development of hepatocellular carcinoma

“…Secondly, FoxM1 is not expressed, or is expressed at very low levels in normal tissues [21]. Thirdly, FoxM1 plays an essential role in HCC cell migration, invasion, as well as liver cancer progression and in cancer cells with stem cell features [15, 22]. Fourthly, clinicopathologic studies suggest that FoxM1 expression correlated with poorly-differentiated HCC tumors with intrahepatic metastasis, which is a leading cause of post-surgical recurrence and low survival rate [20, 29].…”

“…Previous studies have shown that FoxM1 was essential for development of HCC, and overexpression of FoxM1 was associated with aggressive tumor features and poor prognosis [20]. In fact, FoxM1 could induce an epithelial-mesenchymal-like transition phenotype in HCC cells, increase cell migration, and induce premetastatic niche at the distal organ of metastasis [21, 22]. Down-regulation of FoxM1 could suppress the proliferation of HCC cells and inhibit HCC growth [23].…”

FOXM1 is a therapeutic target for high-risk multiple myeloma

“…Further encouraged by new evidence indicating that FOXM1 (1) drives tumor development and progression 15–19 by virtue of a complex mechanism that includes enhanced cell proliferation, migration and invasion 6 , regulation of the DNA damage response 20 and changes in the cancer epigenome 21 , (2) promotes cancer-cell resistance to ionizing radiation 22 and cytotoxic drugs 23 , (3) governs, in part, the survival and tissue-regenerating capacity of both normal hematopoietic stem cells 24 and malignant stem cell-like cells 25 , (4) links acquired resistance to cancer therapy with cancer stemness 26 and (5) owing to the development of specific small-molecule inhibitors 27 , may soon be targeted more effectively than possible in the past 28 , we here decided to evaluate whether FOXM1 might play an important but heretofore overlooked role in plasma cell myeloma.…”