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

Abstract

Purpose: To investigate the expression significance of PPAR b/d in relation to radiotherapy (RT), clinicopathologic, and prognostic variables of rectal cancer patients.Experimental Design: We included 141 primary rectal cancer patients who participated in a Swedish clinical trial of preoperative RT. Tissue microarray samples from the excised rectal cancers and the adjacent or distant normal mucosa and lymph node metastases were stained with PPAR d antibody. Survival probability was computed by the Kaplan-Meier method and Cox regression model. The proliferation of colon cancer cell lines KM12C, KM12SM, and KM12L4a was assayed after PPAR d knockdown.Results: PPAR d was increased from adjacent or distant normal mucosa to primary cancers, whereas it decreased from primary cancers to lymph node metastases. After RT, PPAR d was increased in normal mucosa, whereas it decreased in primary cancers and lymph node metastases. In primary cancers, the high expression of PPAR d was related to higher frequency of stage I cases, lower lymph node metastasis rate, and low expression of Ki-67 in the unirradiated cases, and related to favorable survival in the cases either with or without RT. The proliferation of the KM12C, KM12SM, or KM12L4a cells was significantly accelerated after PPAR d knockdown.Conclusions: RT decreases the PPAR d expression in primary rectal cancers and lymph node metastases. PPAR d is related to the early development of rectal cancer and inhibits the proliferation of colorectal cancer cells. Increase of PPAR d predicts favorable survival in the rectal cancer patients either with or without preoperative RT.

Metastasis regulation by PPARD expression in cancer cells

“…Prior studies of PPARD in humans have reported mixed results. In one report, high PPARD expression levels in human cancers were correlated with advanced stages and metastases (7), but another study indicated that PPARD expression levels in lymph node metastases from rectal cancer were lower than those in paired primary tumors (72). Our newly reported findings in various cancer patient cohorts, including the largest reported cohort of 1,609 breast cancer patients, show that PPARD expression is associated with an increased risk of metastasis and reduced metastasis-free survival.…”

Peroxisome Proliferator-Activated Receptor β/δ Cross Talks with E2F and Attenuates Mitosis in HRAS-Expressing Cells

“…While the role of PPAR␤/␦ in some cancers remains controversial (reviewed in references 45 to 47, 49, and 50), the body of evidence suggesting that PPAR␤/␦ protects against cancer is increasing. For example, a recent compelling study demonstrated that colorectal cancer patients with relatively low expression of PPAR␤/␦ in the primary tumor were ϳ4 times as likely to die from this disease as patients with relatively higher expression of PPAR␤/␦ in their primary tumors (64). It is also not disputed that ligand activation of PPAR␤/␦ inhibits chemically induced skin carcinogenesis (3,4,32,68).…”

Biology and Therapeutic Applications of Peroxisome Proliferator- Activated Receptors

“…PPAR / expression attenuates colon polyp formation and predisposition to intestinal tumorigenesis in C57BL6J-APC min/+ mice and in mice with chemically induced cancers [383,384]. Moreover, a recent study demonstrated that the proliferation of colon cancer cell lines is significantly accelerated after PPAR / knockdown [385]. Finally, in spite of a report suggesting that PPAR / is elevated in most human CDRs [370], other reports show that PPAR / expression is lower in human tumors than in normal control tissues [386].…”