Abstract
As patients with non-muscle-invasive bladder cancer (NMIBC) show a high degree of heterogeneity in tumor recurrence or progression, many clinicians demand a detailed risk stratification. Although modified fatty acid metabolism in cancer cells is reported to reflect malignant phenotypes such as metastasis, the impact of fatty acid transporters on NMIBC has never been investigated. This study examined the clinicopathologic implications of fatty acid transporters such as fatty acid transport protein 4 (FATP4), cluster of differentiation 36/fatty acid translocase (CD36/FAT), and long chain acyl CoA synthetase 1 (ACSL1) in 286 NMIBC cases. This study revealed that FATP4, CD36, and ACSL1 were overexpressed in 123 (43.0%), 43 (15.0%), and 35 (12.2%) NMIBC cases, respectively. High FATP4 in tumor cells was associated with high grade (p = 0.004) and high stage (p = 0.039). High CD36 was related to high grade (p < 0.001), high stage (p = 0.002), and non-papillary growth type (p = 0.004). High ACSL1 showed an association with high grade (p < 0.001), high stage (p = 0.01), non-papillary growth type (p = 0.002), and metastasis (p = 0.033). High FATP4 was an independent factor predicting short overall survival (OS) (hazard ratio = 3.32; 95% confidence interval, 1.07–10.31; p = 0.038). In conclusion, upregulation of FATP4, CD36, and ACSL1 might promote the NMIBC progression and could be exploited in clinical risk stratification and targeted therapy.
Highlights
Urothelial carcinoma has been known to develop via two distinct pathways, non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) [1]
fatty acid transport protein 4 (FATP4), CD36, and ACSL1 were not found in the adjacent normal urothelial cells, whereas the umbrella cells showed occasional positive staining for all these protein markers
High FATP4 expression in tumor cells was associated with high grade (p 0.004) and high stage (p 0.039)
Summary
Urothelial carcinoma has been known to develop via two distinct pathways, non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) [1]. Both subtypes have unique pathological features and different molecular characteristics. More than 70% of newly diagnosed bladder cancers belong to NMIBC, which is characterized morphologically by frequent papillary structures, and genetically by deletion of chromosome 9 and point mutation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 signaling has been suggested to promote the activation of sterol regulatory element-binding protein 1, a key regulator of lipogenesis [2]. Cancer cells require large amounts of fatty acids to supply signaling molecules, basic cellular structural elements, and sources of metabolic energy such as adenosine As patients with NMIBC show extreme heterogeneity in terms of recurrence, progression, and survival rates, detailed risk stratification is required for the optimal management of cancer patients.
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