NF-κB/p65 expression before and after treatment in rectal cancer patients undergoing neoadjuvant (chemo)radiotherapy and surgery: prognostic marker for disease progression and survival

Abstract

Nuclear factor-kappaB (NF-κB), especially p65 subunit, has been associated with origin and progression of cancer as well as with the resistance to radiotherapy and chemotherapy in experimental models. The aim of the present study was to determine expression of NF-κB/p65 in tumor specimens before and after treatment of rectal cancer patients and to evaluate possible relationship between expression of NF-κB/p65 before and after (chemo)radiotherapy, other tumor characteristics and the clinical outcome. Furthermore, NF-κB/p65 was studied in relationship to pathologic response to preoperative (chemo)radiotherapy. Fifty patients with rectal cancer undergoing neoadjuvant (chemo)radiotherapy and surgery were included in the study. Pre-treatment rectal cancer specimens were obtained from diagnostic colonoscopy. Post-treatment rectal cancer specimens were obtained from surgically removed part of the rectum with the tumor. NF-κB/p65 expression was determined by immunohistochemistry and analysis was performed both in biopsies and in post-treatment tumor samples. Cytoplasmic positivity in tumor cells and nuclear positivity in lymphocytes were detected. High NF-κB/p65 positivity in pre-treatment tumor samples was significantly associated with shortened overall survival (OS). Disease-free survival (DFS) tends to be shortened as well. In post-treatment tumor samples, high NF-κB/p65 positivity was neither associated with shortened OS nor with shortened DFS. In post-treatment samples residual tumor cells deeply infiltrating the wall of the rectum with high NF-κB/p65 expression were found. The cells were linked to significantly worse clinical outcome in terms of shortened OS and DFS. NF-κB/p65 positivity did not correlate with pathologic response to preoperative (chemo)radiotherapy. In conclusion, our data suggest that high level of NF-κB/p65 subunit may be associated with more aggressive features of the tumor, higher metastatic potential, and shortened overall survival, but it does not correlate with resistance to (chemo)radiotherapy. Consequently, the level of NF-κB/p65 may help to select those patients who have poor prognosis and are candidates for more intensive anticancer therapy. For these purposes both pre-treatment and post-treatment tumor samples may be used.

Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer

“…Protein biomarkers in tissues have been extensively investigated and the findings were summarized in Table 1. These newly identified protein biomarkers are involved in pathways dysregulated by chemoradiation, including DNA repair (X-ray repair cross-complementing protein 2 (XRCC2) [58], ataxia telangiectasia mutated (ATM) [59], meiotic recombination 11 homolog A (MRE11) [59], PCNA-associated factor 15 (Paf15) [60]), cell cycle (polo-like kinase 1 (Plk1) [61], and vaccinia-related kinase-1 and -2 (VRK1 and VRK2) [62]), cell proliferation (c-MYC and proliferating cell nuclear antigen (PCNA) [63], golgi phosphoprotein 3 (GOLPH3) [64], focal adhesion kinase (FAK) [65], fibroblast growth factor receptor 4 (FGFR4) [66], and nuclear factor-κB (NF-κB) [67]), apoptosis (survivin [68], and apoptotic protease-activating factor 1 (APAF-1) and COX2 [69]), autophagy (Beclin 1 [70]), cell adhesion (Plectin-1 (PLEC1) [71] and desmoglein 3 (DSG3) [72]), cell motility (transgelin (TAGLN) [71]), and metabolism (vascular non-inflammatory molecule 1 (VNN1) [73], transketolase (TKT) and hydroxyacyl-CoA dehydrogenase (HADHA) [71], and 17-β-hydroxysteroid dehydrogenase type 2 (HSD17B2) and 3-hydroxy-3-methylglutaryl coenzyme A synthase (HMGCS2) [74]). Li et al developed a three-protein biomarker panel consisting of c-MYC, PCNA, and tissue inhibitor of metalloproteinases 1 (TIMP1) for prediction of prognosis in 329 locally advanced rectal cancer patients.…”

Differential impact of classical and non-canonical NF-κB pathway-related gene expression on the survival of breast cancer patients

“…Different authors have pointed out that the NF-κB pathway is associated with a poor outcome in another type of cancers: NF-κB/p65 expression was evaluated by IHC in biopsies of 50 patients with rectal cancer undergoing neoadjuvant chemo or radiotherapy and surgery. The results suggested that the high level of NF-κB/p65 is associated with shortened OS [59]. In a different study, it was reported that p50 -/mice had smaller tumors and displayed high levels of IL-12 and CXCL10.…”

PITPNC1 fuels radioresistance of rectal cancer by inhibiting reactive oxygen species production

“…The possibility of developing radioresistance hampers the effect of neoadjuvant radiotherapy and worsens clinical outcomes. Although there have already been many attempts to seek radiosensitivity biomarkers (7)(8)(9)(10)(11)(12), less has been known about the exact mechanisms of the development of radioresistance in rectal cancer, which is vital to improve the therapeutic effect of rectal cancer further and to develop a reliable radiosensitivity evaluation method to optimize clinical decision-making.…”