Loss of protocadherin-17 (PCDH-17) promotes metastasis and invasion through hyperactivation of EGFR/MEK/ERK signaling pathway in hepatocellular carcinoma.

Metastasis has been one of the major reasons for cancer-related mortality, with multiple genes and pathways being involved in this complex process. Given the molecular variations underlying metastasis of hepatocellular carcinoma (HCC) remains largely unknown; in our previous work, we found copying number of protocadherin-17 (PCDH-17) was significantly deleted in HCC tissues that occurred to metastasize compared with that in the primary HCC without metastasis. Therefore, we hypothesized that PCDH-17 may suppress the metastasis of HCC. There has been, however, no relevant literature available regarding PCDH-17 in HCC. In the present study, we have immunohistochemically detected and clinicopathologically analyzed the expression of PCDH-17 in vivo in clinical tissues; besides, we have explored the role of PCDH-17 ex vivo using a panel of HCC cell lines. It was discovered that PCDH-17 expression was clinically correlated with overall prognosis as well as metastasis in vivo and that PCDH-17 inhibited metastasis via EGFR/MEK/ERK signaling pathway ex vivo. Together, our results obtained both in vivo and ex vivo suggested that activation of EGFR/MEK/ERK signaling pathway through PCDH-17 promotes metastasis in HCC.

Beneficial effects of splenectomy on liver regeneration in a rat model of massive hepatectomy.

BACKGROUND: Small-for-size syndrome is a widely recognized clinical complication after living donor liver transplantation or extended hepatectomy due to inadequate liver mass. The purpose of this study was to investigate the role of splenectomy in rats after massive hepatectomy, a surrogate model of small-for-size graft. METHODS: Rats were divided into eight groups, each with 20 animals: 50% hepatectomy (50% Hx), 50% hepatectomy+splenectomy (50% Hx+Sp), 60% Hx, 60% Hx+Sp, 70% Hx, 70% Hx+Sp, 90% Hx and 90% Hx+Sp. The following parameters were evaluated: liver function tests (ALT, AST and TBIL), liver regeneration ratio, DNA synthesis, proliferation cell nuclear antigen, hepatic oxygen delivery (HDO2) and hepatic oxygen consumption (HVO2). RESULTS: The liver regeneration ratio was enhanced in the Hx+Sp groups (P<0.05). In addition, compared with the Hx groups, the Hx+Sp groups had better liver functions (P<0.05). DNA synthesis and proliferation cell nuclear antigen were also increased in the Hx+Sp groups compared with the Hx groups (P<0.05). Furthermore, in the Hx+Sp groups, HDO2 and HVO2 were increased over those in the Hx groups (P<0.05), and were positively correlated with the liver regeneration ratio. CONCLUSIONS: Splenectomy significantly improved liver function, and enhanced DNA synthesis and proliferation cell nuclear antigen after massive hepatectomy in rats. This operation could be mediated through increased HDO2 and HVO2, which facilitate liver regeneration.

Sodium channel Nav1.6 is up-regulated in the dorsal root ganglia in a mouse model of type 2 diabetes.

Neuropathic pain is one of the most common chronic complications of diabetes, of which the underlying mechanisms are unclear. Expression changes of voltage-gated sodium channels in dorsal root ganglia (DRG) are involved in the production of ectopic spontaneous activity. In the present study, we examined the changes of DRG Nav1.6 expression in a mouse model of type 2 diabetes (db/db mice). Db/db mice developed significant and persistent mechanical allodynia from postnatal 2 months compared to the heterozygous littermates (db/+) and C57 mice. Immunofluorescent staining showed that Nav1.6 was highly expressed in the normal DRG (approximately 31.3±5.2% of total DRG neurons), especially in the large-diameter neurons. In postnatal 5 months in db/db mice, percentage of Nav1.6 positive cells (62.9±5.5%) was significantly higher than that in C57 and db/+ mice. Western blot showed that from 2 to 5 months, Nav1.6 was increased by 1.67±0.16, 2.12±0.23, 1.89±0.32, and 2.01±0.35 folds of C57 mice, which were significantly higher than that of the C57 and db/+ mice. Real-time PCR showed that in postnatal 1 month of db/db mice, mRNA level of Nav1.6 was increased by 1.72±0.22 fold, which was significantly higher than that of C57 and db/+ mice. Nav1.6 mRNA was increased thereafter and maintained at high levels throughout the observed period. Our results provide direct evidence that type 2 diabetes induces significant and persistent increase of Nav1.6 expression in the DRG, which may participate in the diabetic neuropathic pain.