Genome-Wide Expression Analysis of Middle Eastern Colorectal Cancer Reveals FOXM1 as a Novel Target for Cancer Therapy

Abstract

To identify genes potentially playing an important role in the progression of colorectal carcinoma (CRC), we screened global gene expression using cDNA expression array on 41 CRC tissue samples and 25 noncancerous colorectal tissue samples. Among the up-regulated genes, forkhead box M1 (FOXM1) has been shown to play a critical role in pathogenesis of various malignancies. Using immunohistochemistry on 448 Saudi CRC samples in tissue microarray format, FoxM1 protein overexpression was seen in 66% of CRC tissues and was significantly associated with poorly differentiated and highly proliferative tumors (P = 0.0200 and 0.0018, respectively). FoxM1 expression was also significantly associated with MMP-9 protein expression (P = 0.0002). In vitro data using CRC cell lines showed that inhibition of FoxM1 by thiostrepton resulted in inhibition of proliferation and induction of apoptosis in a dose-dependent manner. Overexpression of FoxM1 potentiated cell proliferation, cell transformation, and migration/invasion of CRC cells via up-regulation of FoxM1 target genes MMP2 and MMP9 and protected these cells from thiostrepton-mediated antiproliferative effects. Finally, in vivo, overexpression of FoxM1 promoted growth of CRC-cell line xenograft tumors in nude mice. Altogether, our data indicate that FoxM1 signaling contributes to aggressiveness in a subset of CRC and that the FOXM1 gene may serve as a useful molecular biomarker and potential therapeutic target.

Overexpression of FoxM1 offers a promising therapeutic target in diffuse large B-cell lymphoma

“…Immunohistochemical detection of FoxM1 was performed using antibody from Santa Cruz Bio Technology (SCBT, USA, clone K-19) which has been used previously and extensively validated. 9 Antigen retrieval for SKP2, p27, MMP2 and MMP9 was performed for 10 min at 120°C in a pressure cooker at pH6 in Dakocytomation Target retrieval solution (code S2369) and at pH9 in Dako Target retrieval solution (code S2367). 33 We also assessed expression of matrix MMP-9, MMP-2 and Aurora B kinase by immunohistochemistry using X-tile plots as previously described.…”

“…33 We also assessed expression of matrix MMP-9, MMP-2 and Aurora B kinase by immunohistochemistry using X-tile plots as previously described. 9 X-tile plots were constructed for assessment of biomarker and optimization of cut-off points based on outcome as has been described earlier. 32,34,35 The expression of CD10, BCL6 and MUM1 was used to classify tumors as germinal center B-cell (GC), like DLBCL and activated B cell (ABC), applying the decision tree described earlier.…”

“…6,7 Deregulation of FoxM1 has been implicated in the pathogenesis of many cancers because of its ability to drive cell cycle progression and prevention of growth arrest. 8,9 FoxM1 is known to be a key regulator of transition from G1 to S phase by downregulation of p27kip1 through upregulation of S-phase kinase-associated protein 2 (SKP2) and CDK subunit. [10][11][12] FoxM1 has also been known to regulate the transcriptional activity of a number of genes including cyclin B, cyclin A and Aurora B kinase which are very important for cell cycle progression and mitotic entry.…”

“…Recent studies have shown that downregulation of FoxM1 has resulted in inhibition of cell growth, migration and invasion in a number of cancer cells. 9,24,25 FoxM1 has also been shown to be associated with Matrix metalloproteinases (MMPs) in a variety of cancers. MMPs are made up of a large family of related proteolytic enzymes that includes collagenases, gelatinases, stromelysins, elastases, and membrane-type (MTMMPs).…”

Coexpression of Activated c-Met and Death Receptor 5 Predicts Better Survival in Colorectal Carcinoma

“…The tumor volume was measured as previously described. 39 After 5 weeks of treatment, mice were sacrificed and individual tumors were weighted and then snap frozen in liquid nitrogen for storage.…”