Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

Abstract

The role of peroxisome proliferator-activated receptor-b/ d (PPAR-b/d) in the pathogenesis of colon cancer remains highly controversial. This study specifically silenced the PPAR-b expression in three colon cancer cell lines with different metastatic potentials. Although PPAR-b knockdown resulted in more malignant morphological changes, bigger colony sizes and lower carcinoembryonic antigen (CEA) secretion, and enhanced the cell-fibronectin adhesion, cell invasion and migration were unaffected. These effects were stronger in poorly metastatic cell lines compared with highly metastatic ones. Simultaneously, PPAR-b knockdown decreased the mRNAs encoding adipocyte differentiation-related protein and liver fatty acid binding protein, and increased the mRNA of ILK, whereas the mRNAs encoding integrin-b1 and angiopoietin-like 4 were unchanged. Using immunohistochemistry, we determined that the intensity of PPAR-b expression was stronger in rectal cancers with better differentiation than in those with poor differentiation, and was stronger in early-stage tumors than in advanced ones. Together, these findings consistently indicate that PPAR-b may facilitate differentiation and inhibit the cell-fibronectin adhesion of colon cancer, having a role as an inhibitor in the carcinogenesis and progression of colorectal cancer. Interestingly, PPAR-b seems to have a more important role in poorly metastatic cells than in highly metastatic ones.

MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression

“…However, the mechanisms underlying this elevated ILK expression remained unclear. Previous studies showed that ILK expression can be upregulated by hypoxia (Abboud et al, 2007), inhibition of ubiquitin-mediated degradation through binding to PINCH (Legate et al, 2006) or peroxisome proliferator-activated receptor-mediated transcriptional repression (Yang et al, 2010). These data suggest that the cause of ILK upregulation may vary depending on tumor type.…”

“…ILK overexpression and deregulation are frequently observed in a wide variety of human cancers, further implicating ILK in tumorigenesis and cancer progression (Yoganathan et al, 2000;McDonald et al, 2008). Although it is known that ILK protein is stabilized through binding to PINCH (particularly interesting Cys-His-rich protein) (Legate et al, 2006) and that ILK transcription is regulated by peroxisome proliferator-activated receptor (Di-Poi et al, 2002;Yang et al, 2010), the mechanisms of ILK upregulation in cancer cells are poorly understood.…”

Biological Function and Prognostic Significance of Peroxisome Proliferator-Activated Receptor δ in Rectal Cancer

“…Experiments that examined polyp formation in PPAR d-null APC min mice show either no effect (18), or paradoxically, an increase in polyp number and size compared with wildtype mice (13,16,17,19). Our recent study shows that PPAR d may facilitate the differentiation of colon cancer cells (20). Collectively, the role of PPAR d in colorectal carcinogenesis remains highly controversial.…”

“…The expression of PPAR d had been stably silenced in the cells treated by Lenti-PPAR d while remaining unaffected in the Lenticontrol treated cells, as confirmed in our previous study (ref. 20; see Supplementary Data). Of the 3 cell lines, KM12C has poor metastatic potential, whereas KM12SM and KM12L4a have high metastatic potentials (28).…”

“…Fidler, Anderson Cancer Center, Houston, TX), untreated or treated by lentivirus targeting PPAR d gene (Lenti-PPAR d) or by lentivirus without RNA interference effect (Lenti-control) from our previous study (20), were used. All the cell lines were maintained in Eagle's minimal essential medium (MEM) with Earle's salts, l-glutamine and nonessential amino acids (Sigma-Aldrich), supplemented with 1.5% NaHCO3, 1 mm Na-Pyruvate (Invitrogen), 1Â MEM Vitamin Solution (Invitrogen), 1% penicillin-streptomycin (Invitrogen), 1 mg/mL Puromycin (only for the treated cells to maintain the purity) and 10% FBS (Invitrogen).…”