PPDPF Promotes the Development of Mutant KRAS-Driven Pancreatic Ductal Adenocarcinoma by Regulating the GEF Activity of SOS1.

The guanine nucleotide exchange factor (GEF) SOS1 catalyzes the exchange of GDP for GTP on RAS. However, regulation of the GEF activity remains elusive. Here, the authors report that PPDPF functions as an important regulator of SOS1. The expression of PPDPF is significantly increased in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and recurrence of PDAC patients. Overexpression of PPDPF promotes PDAC cell growth in vitro and in vivo, while PPDPF knockout exerts opposite effects. Pancreatic-specific deletion of PPDPF profoundly inhibits tumor development in KRASG12D -driven genetic mouse models of PDAC. PPDPF can bind GTP and transfer GTP to SOS1. Mutations of the GTP-binding sites severely impair the tumor-promoting effect of PPDPF. Consistently, mutations of the critical amino acids mediating SOS1-PPDPF interaction significantly impair the GEF activity of SOS1. Therefore, this study demonstrates a novel model of KRAS activation via PPDPF-SOS1 axis, and provides a promising therapeutic target for PDAC.

BMP10 suppresses hepatocellular carcinoma progression via PTPRS-STAT3 axis.

Bone morphogenetic protein 10 (BMP10), one member of the BMP family, is involved in various development events. Dysregulation of BMP10 has been observed in several diseases, including hypertensive cardiac hypertrophy, Hirschsprung disease and blood vessel formation. However, its role in liver cancer remains largely unknown. In this study, we reported that BMP10 was significantly downregulated in HCC at both mRNA and protein level. Decreased BMP10 was associated with bigger tumor size, worse TNM stage, earlier recurrence and poorer survival. BMP10 negatively regulated HCC cell proliferation in vitro and in vivo. Mechanism study revealed that BMP10 suppressed tumor cell growth by inhibiting STAT3 signaling. Interestingly, we found that cytoplasmic BMP10 interacted with both receptor protein tyrosine phosphatase sigma (PTPRS) and STAT3, which facilitated dephosphorylation of STAT3 by PTPRS. Altogether, our study has revealed the clinical significance of BMP10 in HCC, and suppression of HCC cell growth by BMP10 via PTPRS-STAT3 axis, providing a potential therapeutic strategy for targeting STAT3 signaling in HCC.

CHML promotes liver cancer metastasis by facilitating Rab14 recycle.

Metastasis-associated recurrence is the major cause of poor prognosis in hepatocellular carcinoma (HCC), however, the underlying mechanisms remain largely elusive. In this study, we report that expression of choroideremia-like (CHML) is increased in HCC, associated with poor survival, early recurrence and more satellite nodules in HCC patients. CHML promotes migration, invasion and metastasis of HCC cells, in a Rab14-dependent manner. Mechanism study reveals that CHML facilitates constant recycling of Rab14 by escorting Rab14 to the membrane. Furthermore, we identify several metastasis regulators as cargoes carried by Rab14-positive vesicles, including Mucin13 and CD44, which may contribute to metastasis-promoting effects of CHML. Altogether, our data establish CHML as a potential promoter of HCC metastasis, and the CHML-Rab14 axis may be a promising therapeutic target for HCC.

Liver cancer: WISP3 suppresses hepatocellular carcinoma progression by negative regulation of ß-catenin/TCF/LEF signalling.

OBJECTIVES: Wnt1-inducible signalling pathway protein 3 (WISP3/CCN6) belongs to the CCN (CYR61/CTGF/NOV) family of proteins, dysregulation of this family contributed to the tumorigenicity of various tumours. In this study, we need to explore its role in hepatocellular carcinoma that remains largely elusive. MATERIALS AND METHODS: The expression of WISP3/CCN6 was analysed by qRT-PCR and Western blotting. Effects of WISP3 on proliferation and metastasis of HCC cells were examined, respectively, by MTT assay and Boyden Chamber. Roles of WISP3 on HCC tumour growth and metastatic ability in vivo were detected in nude mice. Related mechanism study was confirmed by immunofluorescence and Western blotting. RESULTS: The expression of WISP3 was significantly downregulated in HCC clinical samples and cell lines, and reversely correlated with the tumour size. Forced expression of WISP3 in HCC cells significantly suppressed cell growth and migration in vitro as well as tumour growth and metastatic seeding in vivo. In contrast, downregulation of WISP3 accelerated cell proliferation and migration, and promoted in vivo metastasis. Further study revealed that WISP3 inhibited the translocation of ß-catenin to the nucleus by activating glycogen synthase kinase-3ß (GSK3ß). Moreover, constitutively active ß-catenin blocked the suppressive effects of WISP3 on HCC. CONCLUSIONS: Our study showed that WISP3 suppressed the progression of HCC by negative regulation of ß-catenin/TCF/LEF signalling, providing WISP3 as a potential therapeutic candidate for HCC.

EphB3 Stimulates Cell Migration and Metastasis in a Kinase-dependent Manner through Vav2-Rho GTPase Axis in Papillary Thyroid Cancer.

Eph receptors, the largest subfamily of transmembrane tyrosine kinase receptors, have been increasingly implicated in various physiologic and pathologic processes, and the roles of the Eph family members during tumorigenesis have recently attracted growing attentions. In the present study, we explored the function of EphB3, one member of Eph family, in papillary thyroid cancer (PTC). We found that the expression of EphB3 was significantly elevated in PTC. Either overexpression of EphB3 or activation of EphB3 by EfnB1-Fc/EfnB2-Fc stimulated in vitro migration of PTC cells. In contrast, siRNA-mediated knockdown of EphB3 or EphB3-Fc treatment, which only blocked EphB3-mediated forward signaling, inhibited migration and metastasis of PTC cells. A mechanism study revealed that EphB3 knockdown led to suppressed activity of Rac1 and enhanced activity of RhoA. Moreover, we found that Vav2, an important regulator of Rho family GTPases, was activated by EphB3 in a kinase-dependent manner. Altogether, our work suggested that EphB3 acted as a tumor promoter in PTC by increasing the in vitro migration as well as the in vivo metastasis of PTC cells through regulating the activities of Vav2 and Rho GTPases in a kinase-dependent manner.

New molecular probe for the selective detection of zinc ion.

A new multisignaling molecular probe DFDB was designed for the selective detection of Zn(2+). DFDB can be synthesized by a simple one-step reaction in high yield. Theoretical calculation suggests a novel sandwich structure of the DFDB·Zn(2+) complex.