No abstract

Aberrant expression of Forkhead box (FOX) transcription factors plays vital roles in carcinogenesis. However, the function of the FOX family member FOXC1 in maintenance of colorectal cancer (CRC) malignancy is unknown. Herein, FOXC1 expression in CRC specimens in The Cancer Genome Atlas (TCGA) cohort was analyzed and validated using immunohistochemistry with a tissue microarray. The effect of FOXC1 expression on proliferation of and glycolysis in CRC cells was assessed by altering its expression in vitro and in vivo. Mechanistic investigation was carried out using cell and molecular biological approaches. Our results showed that FOXC1 expression was higher in CRC specimens than in adjacent benign tissue specimens. Univariate survival analyses of the patients from whom the study specimens were obtained, and validated cohorts indicated that ectopic FOXC1 expression was significantly correlated with shortened survival. Silencing FOXC1 expression in CRC cells inhibited their proliferation and colony formation and decreased their glucose consumption and lactate production. In contrast, FOXC1 overexpression had the opposite effect. Furthermore, increased expression of FOXC1 downregulated that of a key glycolytic enzyme, fructose-1,6-bisphosphatase 1 (FBP1). Mechanistically, FOXC1 bound directly to the promoter regions of the FBP1 gene and negatively regulated its transcriptional activity. Collectively, aberrant FBP1 expression contributed to CRC tumorigenicity, and decreased FBP1 expression coupled with increased FOXC1 expression provided better prognostic information than did FOXC1 expression alone. Therefore, the FOXC1/FBP1 axis induces CRC cell proliferation, reprograms metabolism in CRCs, and constitutes potential prognostic predictors and therapeutic targets for CRC.

Objectives To evaluate predictors of long‐term survival for patients with chronic kidney disease primarily due to surgery (CKD‐S). Patients with CKD‐S have generally good survival that approximates patients who do not have CKD even after renal cancer surgery (RCS), yet there may be heterogeneity within this cohort. Patients and Methods From 1997 to 2008, 4 246 patients underwent RCS at our centre. The median (interquartile range [IQR]) follow‐up was 9.4 (7.3–11.0) years. New baseline glomerular filtration rate (GFR) was defined as highest GFR between nadir and 6 weeks after RCS. We retrospectively evaluated three cohorts: no‐CKD (new baseline GFR of ≥60 mL/min/1.73 m2); CKD‐S (new baseline GFR of <60 mL/min/1.73 m2 but preoperative GFR of ≥60 mL/min/1.73 m2); and CKD due to medical aetiologies who then require RCS (CKD‐M/S, preoperative and new baseline GFR both <60 mL/min/1.73 m2). Analysis focused primarily on non‐renal cancer‐related survival (NRCRS) for the CKD‐S cohort. Kaplan–Meier analysis assessed the longitudinal impact of new baseline GFR (45–60 mL/min/1.73 m2 vs <45 mL/min/1.73 m2) and Cox regression evaluated relative impact of preoperative GFR, new baseline GFR, and relevant demographics/comorbidities. Results Of the 4 246 patients who underwent RCS, 931 had CKD‐S and 1 113 had CKD‐M/S, whilst 2 202 had no‐CKD even after RCS. Partial/radical nephrectomy (PN/RN) was performed in 54%/46% of the patients, respectively. For CKD‐S, 641 patients had a new baseline GFR of 45–60 mL/min/1.73 m2 and 290 had a new baseline GFR of <45 mL/min/1.73 m2. Kaplan–Meier analysis showed significantly reduced NRCRS for patients with CKD‐S with a GFR of <45 mL/min/1.73 m2 compared to those with no‐CKD or CKD‐S with a GFR of 45–60 mL/min/1.73 m2 (both P ≤ 0.004), and competing risk analysis confirmed this (P < 0.001). Age, gender, heart disease, and new baseline GFR were all associated independently with NRCRS for patients with CKD‐S (all P ≤ 0.02). Conclusion Our data suggest that CKD‐S is heterogeneous, and patients with a reduced new baseline GFR have compromised survival, particularly if <45 mL/min/1.73 m2. Our findings may have implications regarding choice of PN/RN in patients at risk of developing CKD‐S.

Acute kidney injury after partial nephrectomy was not a significant or independent predictor of long-term functional decline in our institutional cohort. A prospective study with larger sample sizes and longer followup is required to evaluate factors associated with long-term nephron stability.