Prognostic value of c-FLIPL/s, HIF-1α, and NF-κβ in stage II and III rectal cancer

Abstract

Locally advanced rectal cancer (LARC) is associated with a 25 % rate of metastases. The prognostic and predictive relevances of the expression of five proteins (c-FLIPL/s, HIF-1α, β-catenin, p65, and p105/p50 NF-κβ) were assessed. This is a retrospective study. From 1998 to 2009, 152 patients with stage II/III rectal cancer were treated with radio-chemotherapy. TMAs constructed with tumor and normal tissue from the diagnostic endoscopic biopsy and the surgical specimen after chemoradiotherapy were subjected to immunohistochemical (IHC) analysis. Results were correlated with clinical and pathological data, including progression-free survival (PFS). Four different IHC conditions were independent prognostic parameters for PFS: (1) cytoplasmic c-FLIPL/s (p = 0.007), (2) nuclear HIF-1α (p = 0.020), (3) a change in the cytoplasmic p65 between the diagnostic biopsy and the post-treatment specimen (p = 0.004), and (4) a change in the cytoplasmic c-FLIPL/s between the diagnostic biopsy and the post-treatment specimen (p = 0.021). Three different protein expression profiles, combining biomarkers, showed prognostic significance. IHC evaluation of these biomarkers in our three protein expression profiles may help to identify patients with worse prognosis and design more effective therapeutic strategies to personalize the treatment of rectal cancer.

Hypoxia attenuates the proinflammatory response in colon cancer cells by regulating IκB

“…Mortality of colorectal cancer patients has previously been demonstrated to be associated with high HIF-1α, but not HIF-2α, mRNA and protein levels [ 24 , 25 ]. The mouse model of colorectal cancer used in this study shows similar features: HIF-2α mRNA levels in MC-38 colon adenocarcinoma cells were at least two orders of magnitude lower than the HIF-1α mRNA levels.…”

“…NF-κB plays an important role during colorectal cancer progression and NF-κB has been shown to be a prognostic factor negatively associated with survival in patients with metastatic colorectal cancer [ 25 , 27 ]. Colorectal cancer cells are likely to be exposed to bacterial LPS, derived from the gut microbiota, which is known to activate NF-κB via Toll-like receptor 4 (TLR4).…”

Immunohistochemical evidence of stress and inflammatory markers in mouse models of cutaneous leishmaniosis

“…Considering the needs to identify biomarkers to leishmaniasis that can be used to diagnose disease, predict clinical outcome, monitor therapeutic responses and immunity [33,40], we have examined the tissue expression of some inflammatory and stress markers during cutaneous murine leishmaniosis. The predictive or diagnostic values of proteins markers have been suggested for many diseases, for example, hypoxia-inducible factor (HIF-1a) for rectal cancer [43], heme oxygenase (HO-1) for malaria [4] and bladder cancer [41], vascular endothelial growth factor (VEGF) for Sjögren's syndrome [60] and CD31/VEGF for asthma [54]. Thus, similar knowledge could help to determine the relevance of different host mediators in relation to leishmaniasis control or exacerbation and their predictive value.…”

Tumor cell endogenous HIF-1α activity induces aberrant angiogenesis and interacts with TRAF6 pathway required for colorectal cancer development

“…Since HIF-1α expression in colorectal cancer correlates with poor prognosis [32 , 33] , we examined human colorectal tumor samples in the Medisapiens database ( http://ist.medisapiens.com/ ) for the expression of HIF-1α and transcripts identified to be dysregulated in HIF-1α-KD tumor cells. The analysis of 991 patients dataset showed a direct correlation between HIF-1Α mRNA levels and LOX, CYR61, PGTS2, SOCS3, TIMP3, PELI1, TNFRSF9, and ANGPTL4 (Supplementary Figure 4A), which is in agreement with data obtained from the MC-38 mouse model.…”