The Tumor Suppressive Role of eIF3f and Its Function in Translation Inhibition and rRNA Degradation

Deregulated translation plays an important role in human cancer. We previously reported decreased eukaryotic initiation factor 3 subunit f (eIF3f) expression in pancreatic cancer. Whether decreased eIF3f expression can transform normal epithelial cells is not known. In our current study, we found evidence that stable knockdown of eIF3f in normal human pancreatic ductal epithelial cells increased cell size, nuclear pleomorphism, cytokinesis defects, cell proliferation, clonogenicity, apoptotic resistance, migration, and formation of 3-dimensional irregular masses. Our findings support the tumor suppressive role of eIF3f in pancreatic cancer. Mechanistically, we found that eIF3f inhibited both cap-dependent and cap-independent translation. An increase in the ribosomal RNA (rRNA) level was suggested to promote the generation of cancer. The regulatory mechanism of rRNA degradation in mammals is not well understood. We demonstrated here that eIF3f promotes rRNA degradation through direct interaction with heterogeneous nuclear ribonucleoprotein (hnRNP) K. We showed that hnRNP K is required for maintaining rRNA stability: under stress conditions, eIF3f dissociates hnRNP K from rRNA, thereby preventing it from protecting rRNA from degradation. We also demonstrated that rRNA degradation occurred in non-P body, non-stress granule cytoplasmic foci that contain eIF3f. Our findings established a new mechanism of rRNA decay regulation mediated by hnRNP K/eIF3f and suggest that the tumor suppressive function of eIF3f may link to impaired rRNA degradation and translation

The sonic hedgehog signaling pathway induces myopic development by activating matrix metalloproteinase (MMP)-2 in Guinea pigs.

PURPOSE: To investigate whether the Sonic hedgehog (Shh) signaling induces myopic development by increasing the expression of matrix metalloproteinase (MMP)-2 in guinea pigs. METHODS: A translucent diffuser was glued onto the right eye to induce form-deprivation myopia (FDM) in 10 guinea pigs. Four guinea pigs were served as a control group. The other 100 guinea pigs were subdivided into 5 groups (20 per group) and received a 10 µl intravitreal injection every 2 days for 4 times. Two groups were injected with 20 or 50 µg/ml Shh amino-terminal peptide (Shh-N) into the right eye and 0.1% bovine serum albumin into the other. FDM was induced in the right eyes of the three cyclopamine-treated groups and both eyes were injected with 50, 100, or 200 µg/ml cyclopamine. Retinoscopic refraction and eye dimensions were assessed on Day 14 of treatment. MMP-2 protein expression was determined in both scleras by western blotting. RESULTS: Both concentrations of Shh-N stimulated myopic development and axial growth as compared with control eyes. Myopia and axial elongation were significantly greater in the 50 µg/ml than in the 20 µg/ml Shh-N group (P<0.001 and P = 0.0019, respectively). All three doses of cyclopamine significantly attenuated myopic development compared with the FDM group (P<0.0001). Cyclopamine at 100 or 200 µg/ml significantly reduced axial elongation compared with the FDM group (P = 0.044 and P = 0.001, respectively). FDM-induced myopia and axial elongation were significantly greater in the 50 µg/ml than in the 200 µg/ml cyclopamine group (P<0.0001 and P = 0.008, respectively). MMP-2 expression was significantly greater in Shh-N-treated eyes than in the control eyes, and was lower in the cyclopamine plus FDM groups than in the FDM group. CONCLUSIONS: The Shh signaling pathway induces myopic development by activating MMP-2 in guinea pigs

Western blotting analysis of MMP-2 protein expression in the sclera of guinea pigs following FDM and intravitreal cyclopamine injection.

<p>FDM: form-deprivation myopia; Cyclo: cyclopamine; R: right eye; L: left eye; MMP-2: matrix metalloproteinase-2.</p

Experimental groups and reasons for excluding guinea pigs with FDM and treated with cyclopamine.

<p>FDM: form-deprivation myopia; Cyclo: cyclopamine.</p

Experimental groups and reasons for excluding guinea pigs treated with Shh-N.

<p>Shh-N: Shh amino-terminal peptide.</p

Pathologic examination of eye sections stained with hematoxylin and eosin.

<p>The retina of eyes treated with Shh-N (B) were morphologically indistinguishable from control eyes treated with solvent alone (A). Shh-N: Shh amino-terminal peptide.</p

Progression of White Matter Hyperintensities Contributes to Lacunar Infarction

Both white matter hyperintensities (WMHs) and lacunar infarctions (LIs) are magnetic resonance imaging (MRI) markers of cerebral small vessel disease (SVD). However, the association between WMH and LI remains unclear. In this study, we asked whether WMH progression is related to LI occurrence using retrospective data. Overall, 8475 WMH patients with at least two MRI images were screened, and 187 patients were included in the final study; 76 patients had WMH with LI (WL), and 111 patients had WMH without LI (WOL). The 187 patients were divided into three groups according to WMH progression: Group 1 (no progression), Group 2 (0-53.64% WMH progression) and Group 3 (≥53.64% WMH progression). We found that both WMH volumes and Fazekas scores were higher in WL patients compared with those in WOL patients according to the 1st and 2nd MRI images (P0.05). Importantly, we found that the occurrence rates for LI were increased in Groups 2 and 3 compared with those in Group 1. Multiple logistic regression analysis demonstrated that the risk of LI occurrence was significantly increased in Group 2 versus that in Group 1 (odds ratio, 3.36; 95% CI, 1.48 to 7.67; P=0.004) after adjusting for the baseline patient characteristics and the interval between the two MRI scans. Additionally, with a stratification time of less than 24 months, the risk of LI occurrence was higher in Group 2 versus that in Group 1, after adjusting for baseline confounding factors (odds ratio, 3.68; 95% CI, 1.51 to 8.99; P=0.004). In conclusion, we found that WMH progression was significantly associated with LI occurrence, particularly within the first two years, and that this progression could serve as an independent indicator of LI development