Prognostic value of pigment epithelium-derived factor for neoadjuvant radiation therapy in patients with locally advanced rectal carcinoma

Abstract

The aim of the study was to investigate the prognostic value of pigment epithelium-derived factor (PEDF) in locally advanced rectal carcinoma (LARC) treated with neoadjuvant radiation therapy (nRT). The level of PEDF expressing was examined in LARC tissues treated with nRT by immunohistochemistry and the prognostic significance of PEDF was analysed by univariate and multivariate survival analyses. We forced expression of PEDF in highly metastatic LoVo cells. The clonogenic survival assay was used to test the cellular sensitivity to radiation. Wound healing and Boyden chamber assays were used to detect cell migration and invasion. To assess the contribution of PEDF in vivo, we established tumor xenografts. The mechanisms of PEDF on cancer cells was analysed by bioinformatics. Our immunohistochemical staining of tissue samples revealed that prolonged DFS (77.1 vs 49.0%) and OS (87.1 vs 56.3%) was observed in PEDF-positive cases (P<0.001) following nRT. PEDF could be an independent factor for DFS [P=0.001; HR, 0.422 (95% CI, 0.249-0.717)] and OS [P=0.003; HR, 0.418 (95% CI, 0.234-0.749)]. Positive-expression of PEDF was negatively correlated with tumor differentiation (P<0.016), ypT stage (P<0.037), ypTNM stage (P<0.033), and ypN stage (P=0.006). Overexpression of PEDF in high metastatic cells enhanced radiosensitivity and, suppressed migration and invasion in vitro. In tumor xenografts, PEDF significantly suppressed tumor growth. Furthermore, by bioinformatics analysis, we found PEDF performs functions via activating P53 to regulate double-strand break repair pathway and activate the G protein activation pathway. Our findings indicate that PEDF was identified as a predictive candidate for nRT responsiveness. These findings may be used to stratify LARC patients and make alternative strategies for adjuvant treatment.

Genetic Regulation of Pigment Epithelium-Derived Factor (PEDF): An Exome-Chip Association Analysis in Chinese Subjects With Type 2 Diabetes

“…Histone lysine methylation and DNA methylation are highly interrelated, and these two systems rely on each other mechanistically for normal chromatin function (43,44). One previous study showed that PEDF promoter methylation status negatively correlated with the PEDF mRNA expression level in locally advanced rectal carcinoma tissues (45). Therefore, SMYD4 may influence PEDF expression via its potential effect on epigenetic modification.…”

Association of pigment epithelium derived factor expression with cancer progression and prognosis: a meta-analysis study

“…Specifically, Hou et al [ 37 ], Yi et al . [ 38 ], and Jiang et al [ 39 ] grouped tumors with grade G1-2 to be “low grade” and tumors with grade G3-4 to be “high grade”. Zhou et al [ 40 ] and Uehara et al [ 41 ] defined G1 tumors as “low grade” and G2-3 tumors as “high grade”; while Jang et al [ 39 ] did not provide grading information for the “low grade” and “high grade” groups in their study.…”

“…Other than TNM stating, we are also interested in the association of PEDF protein expression with tumor histological grades. While reviewing the original studies, we noticed that tumors had been categorized into "low-grade" and Zhang [42] Li [43] Hou [37] Yi [38] Uehara [41] Jang [55] Lv [56] Jiang [39] Publication year "high-grade" groups based on the conventional cut-off criteria of each type of cancer (Table 1). Specifically, Hou et al [37], Yi et al [38], and Jiang et al [39] grouped tumors with grade G1-2 to be "low grade" and tumors with grade G3-4 to be "high grade".…”

“…While reviewing the original studies, we noticed that tumors had been categorized into "low-grade" and Zhang [42] Li [43] Hou [37] Yi [38] Uehara [41] Jang [55] Lv [56] Jiang [39] Publication year "high-grade" groups based on the conventional cut-off criteria of each type of cancer (Table 1). Specifically, Hou et al [37], Yi et al [38], and Jiang et al [39] grouped tumors with grade G1-2 to be "low grade" and tumors with grade G3-4 to be "high grade". Zhou et al [40] and Uehara et al [41] defined G1 tumors as "low grade" and G2-3 tumors as "high grade"; while Jang et al [39] did not provide grading information for the "low grade" and "high grade" groups in their study.…”

Predictive value of proteomic markers for advanced rectal cancer with neoadjuvant chemoradiotherapy

“…Serum APOA1 level showed strong negative correlation with CRP and interleukin IL-8 levels and blood neutrophil count [ 43 ]. Our previous work showed that patients with high PEDF expression after nRT had better DFS in rectal cancer [ 44 ]. This study further implicated that PEDF might be a prognostic marker.…”