Impact of Sulfatase-2 on cancer progression and prognosis in patients with renal cell carcinoma.

Heparan sulfate-specific endosulfatase-2 (SULF-2) can modulate the signaling of heparan sulfate proteoglycan-binding proteins. The involvement of SULF-2 in cancer growth varies by cancer type. The roles of SULF-2 expression in the progression and prognosis of renal cell carcinomas (RCC) have not yet been fully clarified. In the present study, the expression levels of SULF-2 mRNA and protein in 49 clinical RCC samples were determined by RT-PCR and immunostaining. The existence of RCC with higher SULF-2 expression and lower SULF-2 expression compared to the adjacent normal kidney tissues was suggested. High SULF-2 expression was correlated with an early clinical stage and less invasive pathological factors. Low SULF-2 expression was correlated with an advanced stage and higher invasive factors. Three-year cancer-specific survival (CSS) for high SULF-2 RCC and low SULF-2 RCC were 100% and 71.4%, respectively (log-rank P = 0.0019), with a significantly shorter CSS observed in low SULF-2 RCC patients. The influence of SULF-2 expression level on Wnt/VEGF/FGF signaling, cell viability and invasive properties was examined in three RCC cell lines, Caki-2, ACHN and 786-O, using a SULF-2 suppression model involving siRNA or a SULF-2 overexpression model involving a plasmid vector. High SULF-2 expression enhanced Wnt signaling and Wnt-induced cell viability, but not cell invasion. In contrast, low levels of SULF-2 expression significantly enhanced both cell invasion and viability through the activation of VEGF/FGF pathways. RCC with lower SULF-2 expression might have a higher potential for cell invasion and proliferation, leading to a poorer prognosis via the activation of VEGF and/or FGF signaling.

Familial hypertrophic obstructive cardiomyopathy with the GLA E66Q mutation and zebra body.

BACKGROUND: Fabry disease is caused by mutations in the α-galactosidase A (GLA) gene, which is located in X-chromosome coding for the lysosomal enzyme of GLA. Among many gene mutations, E66Q mutation is under discussion for its pathogenicity because there is no clinical report showing pathological evidence of Fabry disease with E66Q mutation. CASE PRESENTATION: A 65-year-old Japanese female was referred to our hospital for chest discomfort on effort. Transthoracic echocardiography showed severe left ventricular (LV) hypertrophy with LV outflow obstruction. Maximum LV outflow pressure gradient was 87 mmHg, and Valsalva maneuver increased the pressure gradient up to 98 mmHg. According to medical interview, one of her younger sister and a nephew died suddenly at age 42 and 36, respectively. Another younger sister also presented LV hypertrophy with outflow obstruction. Maximum LV outflow pressure gradient was 100 mmHg, and the E66Q mutation was detected similar to the case. Endomyocardial biopsy specimens presented vacuolation of cardiomyocytes, in which zebra bodies were detected by electron microscopic examination. Although the enzymatic activity of GLA was within normal range, the c. 196G>C nucleotide change, which lead to the E66Q mutation of GLA gene, was detected. We initially diagnosed her as cardiac Fabry disease based on the findings of zebra body. However, immunostaining showed few deposition of globotriaosylceramide in left ventricular myocardium, and gene mutations in the disease genes for hypertrophic cardiomyopathy (HCM), MYBPC3 and MYH6, were detected. Although the pathogenicity of the E66Q mutation cannot be ruled out, hypertrophic obstructive cardiomyopathy (HOCM) was more reasonable to explain the pathophysiology in the case. CONCLUSIONS: This is the confusable case of HOCM with Fabry disease with the GLA E66Q mutation. We have to take into consideration the possibility that some patients with the E66Q mutation may have similar histological findings of Fabry disease, and should be examed the possibility for harboring gene mutations associated with HCM.