Downregulation of Fumarate Hydratase Is Related to Tumorigenesis in Sporadic Renal Cell Cancer

Abstract

Objective: Although germline mutations of fumarate hydratase(FH) are a useful molecular marker of hereditary leiomyomatosis and renal cell cancer (RCC) syndrome, their clinical significance in sporadic RCC has not been studied in detail. The aim of the present study was to investigate possible correlations between the expression of FH and the clinical implications of sporadic RCC. Materials and Methods:FH mRNA levels were evaluated in 140 tumor specimens from patients with primary RCC and in 62 specimens of corresponding normal-appearing kidney tissue using real-time quantitative polymerase chain reaction. Immunohistochemical staining was performed on 6 normal surrounding tissues and 71 RCC tissues. Results:FH mRNA levels were significantly lower in tumor tissues than in matched normal-appearing kidney tissues (p = 0.031). In all normal tissues, FH staining intensity was strong. However, the expression of FH showed no significant correlation with the pathological and clinical characteristics of patients with sporadic RCC. Conclusions: Our results showed that FH mRNA expression decreased significantly in correlation with the transition from normal renal parenchyma to RCC. FH may be an indicator or tumorigenesis in sporadic RCC and could be a potential target for therapies against RCC in the future.

Fumarate hydratase in cancer: A multifaceted tumour suppressor

“…1C). Consistent with a broader role of FH in tumorigenesis, its transcriptional downregulation was found in sporadic clear cell carcinomas [30] and in colorectal cancer [31], and additional evidence suggests the involvement of FH mutations in breast, bladder, and testicular cancers [32]. These findings hint at a key role of FH loss in human cancers.…”

The Significance of Mitochondrial Dysfunction in Cancer

“…Patients with heterozygous germline mutations in the FH gene are susceptible to multiple cutaneous and uterine leiomyomatosis (MCUL), which is associated with an increased risk of developing papillary renal cell cancer and leiomyosarcoma ( Table 1 ) [ 35 , 36 , 37 ]. The sporadic loss of FH or transcriptional downregulation of FH was found in various cancers, such as pheochromocytomas, paragangliomas, neuroblastomas, adrenocortical carcinoma, ependymoma, osteosarcoma, bladder cancer, breast cancer, glioma, colorectal cancer, and testicular cancers [ 38 , 39 , 40 , 41 , 42 , 43 ]. Inactivation of FH compromises the TCA cycle and respiration, and tumor cells harboring mutations in FH were found to adapt to the glutamine-dependent reductive carboxylation reactions as an alternative pathway for the formation of αKG and citrate, which fuel the TCA cycle and generate NADH to feed into the electron transport chain for ATP generation and the maintenance of mitochondrial membrane potential [ 44 ].…”

Oncometabolites in cancer aggressiveness and tumour repopulation

“…FH germline mutations, which are often missense mutations and are particularly frequent in exons 4, 5, 7 and 8 (Bayley, Launonen, & Tomlinson, ; Picaud et al , ; Yoshinaga et al , ), have been found to decrease FH activity with the consequent accumulation of fumarate. Decreased functionality of FH predisposes individuals to several pathologies including multiple cutaneous leiomyomas, uterine leiomyomas, and the familial syndrome hereditary leiomyomatosis and renal cell cancer (HLRCC), which causes smooth muscle tumours and renal cell carcinomas (Bayley et al , ; Ha et al , ). HLRCC frequently involves a R190H mutation on the FH gene, which generates a dominant negative protein (Lorenzato et al , ).…”