RACK1 suppresses gastric tumorigenesis by stabilizing the ß-catenin destruction complex.

BACKGROUND & AIMS: Dysregulation of Wnt signaling has been involved in gastric tumorigenesis by mechanisms that are not fully understood. The receptor for activated protein kinase C (RACK1, GNB2L1) is involved in development of different tumor types, but its expression and function have not been investigated in gastric tumors. METHODS: We analyzed expression of RACK1 in gastric tumor samples and their matched normal tissues from 116 patients using immunohistochemistry. Effects of knockdown with small interfering RNAs or overexpression of RACK1 in gastric cancer cell lines were evaluated in cell growth and tumor xenograft. RACK1 signaling pathways were investigated in cells and zebrafish embryos using immunoblot, immunoprecipitation, microinjection, and in situ hybridization assays. RESULTS: Expression of RACK1 was reduced in gastric tumor samples and correlated with depth of tumor infiltration and poor differentiation. Knockdown of RACK1 in gastric cancer cells accelerated their anchorage-independent proliferation in soft agar, whereas overexpression of RACK1 reduced their tumorigenicity in nude mice. RACK1 formed a complex with glycogen synthase kinase Gsk3ß and Axin to promote the interaction between Gsk3ß and ß-catenin and thereby stabilized the ß-catenin destruction complex. On stimulation of Wnt3a, RACK1 repressed Wnt signaling by inhibiting recruitment of Axin by Dishevelled 2 (Dvl2). Moreover, there was an inverse correlation between expression of RACK1 and localization of ß-catenin to the cytoplasm/nucleus in human gastric tumor samples. CONCLUSIONS: RACK1 negatively regulates Wnt signaling pathway by stabilizing the ß-catenin destruction complex and act as a tumor suppressor in gastric cancer cells.

Cilia loss sensitizes cells to transformation by activating the mevalonate pathway.

Although cilia loss and cell transformation are frequently observed in the early stage of tumorigenesis, the roles of cilia in cell transformation are unknown. In this study, disrupted ciliogenesis was observed in cancer cells and pancreatic cancer tissues, which facilitated oncogene-induced transformation of normal pancreatic cells (HPDE6C7) and NIH3T3 cells through activating the mevalonate (MVA) pathway. Disruption of ciliogenesis up-regulated MVA enzymes through ß catenin-T cell factor (TCF) signaling, which synchronized with sterol regulatory element binding transcription factor 2 (SREBP2), and the regulation of MVA by ß-catenin-TCF signaling was recapitulated in a mouse model of pancreatic ductal adenocarcinoma (PDAC) and human PDAC samples. Moreover, disruption of ciliogenesis by depleting Tg737 dramatically promoted tumorigenesis in the PDAC mouse model, driven by KrasG12D , which was inhibited by statin, an inhibitor of the MVA pathway. Collectively, this study emphasizes the crucial roles of cilia in governing the early steps of the transformation by activating the MVA pathway, suggesting that statin has therapeutic potential for pancreatic cancer treatment.

[Changes of plasma fibrinolysis system and the effect of captopril in high altitude pulmonary edema].

OBJECTIVE: To investigate the changes of plasma fibrinolysis system and the effect of captopril in patients with high altitude pulmonary edema. METHODS: The plasma levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) were measured before and after treatment in the captopril-group (group A, 35 cases) and the routine-group (group B, 37 cases) of patients with HAPE, while 20 healthy volunteers served as the control (group C). RESULTS: The plasma level of tPA was (0.40 +/- 0.14) x 10(3) IU/L in group A vs (0.39 +/- 0.19) x 10(3) IU/L in group B before treatment, and (0.58 +/- 0.13) x 10(3) IU/L vs (0.49 +/- 0.16) x 10(3) IU/L after treatment, and (0.59 +/- 0.17) x 10(3) IU/L in group C. The differences were significant both before and after treatment between group A and group B (P < 0.01, P < 0.05). While PAI-1 was (6.6 +/- 1.8) x 10(3) AU/L in group A vs (6.6 +/- 1.6) x 10(3) AU/L in group B before treatment, and (4.9 +/- 1.5) x 10(3) AU/L vs (5.8 +/- 1.7) x 10(3) AU/L after treatment, and (4.9 +/- 1.3) x 10(3) AU/L in group C. The differences were significant both before and after treatment between group A and group B (P < 0.01, P < 0.05). CONCLUSION: Patients with HAPE may present a disturbance of the fibrinolysis system, which could be reversed by captopril.

Heterochromatin protein 1 promotes self-renewal and triggers regenerative proliferation in adult stem cells.

Adult stem cells (ASCs) capable of self-renewal and differentiation confer the potential of tissues to regenerate damaged parts. Epigenetic regulation is essential for driving cell fate decisions by rapidly and reversibly modulating gene expression programs. However, it remains unclear how epigenetic factors elicit ASC-driven regeneration. In this paper, we report that an RNA interference screen against 205 chromatin regulators identified 12 proteins essential for ASC function and regeneration in planarians. Surprisingly, the HP1-like protein SMED-HP1-1 (HP1-1) specifically marked self-renewing, pluripotent ASCs, and HP1-1 depletion abrogated self-renewal and promoted differentiation. Upon injury, HP1-1 expression increased and elicited increased ASC expression of Mcm5 through functional association with the FACT (facilitates chromatin transcription) complex, which consequently triggered proliferation of ASCs and initiated blastema formation. Our observations uncover an epigenetic network underlying ASC regulation in planarians and reveal that an HP1 protein is a key chromatin factor controlling stem cell function. These results provide important insights into how epigenetic mechanisms orchestrate stem cell responses during tissue regeneration.