Linear-array EUS improves the accuracy of predicting deep submucosal invasion in non-pedunculated rectal polyps compared with radial EUS: a prospective observational study.

BACKGROUND: Radial endoscopic ultrasound (EUS) is typically used to estimate the depth of rectal polyp invasion, however, there are no data on linear EUS in this setting and its relative accuracy compared to radial EUS. METHODS: In this prospective cohort study, 89 patients with non-pedunculated rectal polyp who underwent linear EUS or radial EUS were prospectively enrolled. The invasion depth was measured for each polyp and categorized as mucosal to shallow submucosal(SMs) or deep submucosal(SMd) invasion. Invasion measurements were compared with the final diagnosis on histopathology. RESULTS: A total of 58 patients underwent radial EUS and 31 patients underwent linear EUS examination. There were 38 lesions correctly diagnosed in the radial EUS group and 29 correctly diagnosed lesions in the linear EUS group. The diagnostic accuracy of SMd invasion for linear EUS was significantly higher than radial EUS (0.936 vs. 0.655, p = 0.003). A significant difference was also noted for specificity between the two groups (0.963 vs. 0.659, p = 0.003). Univariate analysis showed radial EUS type (OR 0.131, 95% CI 0.028-0.606, p = 0.009) to be an independent predictor for incorrect diagnosis. The area under the receiver operating curve (ROC) was 0.856 and 0.651 for linear EUS and radial EUS, respectively. It was noted that four patients underwent unnecessary surgery for radial EUS while there were no such patients in the linear EUS group. CONCLUSIONS: Linear EUS was more accurate for determining SMd invasion and contributed to the selection of appropriate treatment modalities in patients with non-pedunculated rectal polyp.

N-glycosylation-defective splice variants of neuropilin-1 promote metastasis by activating endosomal signals.

Neuropilin-1 (NRP1) is an essential transmembrane receptor with a variety of cellular functions. Here, we identify two human NRP1 splice variants resulting from the skipping of exon 4 and 5, respectively, in colorectal cancer (CRC). Both NRP1 variants exhibit increased endocytosis/recycling activity and decreased levels of degradation, leading to accumulation on endosomes. This increased endocytic trafficking of the two NRP1 variants, upon HGF stimulation, is due to loss of N-glycosylation at the Asn150 or Asn261 site, respectively. Moreover, these NRP1 variants enhance interactions with the Met and ß1-integrin receptors, resulting in Met/ß1-integrin co-internalization and co-accumulation on endosomes. This provides persistent signals to activate the FAK/p130Cas pathway, thereby promoting CRC cell migration, invasion and metastasis. Blocking endocytosis or endosomal Met/ß1-integrin/FAK signaling profoundly inhibits the oncogenic effects of both NRP1 variants. These findings reveal an important role for these NRP1 splice variants in the regulation of endocytic trafficking for cancer cell dissemination.

Snail determines the therapeutic response to mTOR kinase inhibitors by transcriptional repression of 4E-BP1.

Loss of 4E-BP1 expression has been linked to cancer progression and resistance to mTOR inhibitors, but the mechanism underlying 4E-BP1 downregulation in tumors remains unclear. Here we identify Snail as a strong transcriptional repressor of 4E-BP1. We find that 4E-BP1 expression inversely correlates with Snail level in cancer cell lines and clinical specimens. Snail binds to three E-boxes present in the human 4E-BP1 promoter to repress transcription of 4E-BP1. Ectopic expression of Snail in cancer cell lines lacking Snail profoundly represses 4E-BP1 expression, promotes cap-dependent translation in polysomes, and reduces the anti-proliferative effect of mTOR kinase inhibitors. Conversely, genetic and pharmacological inhibition of Snail function restores 4E-BP1 expression and sensitizes cancer cells to mTOR kinase inhibitors by enhancing 4E-BP1-mediated translation-repressive effect on cell proliferation and tumor growth. Our study reveals a critical Snail-4E-BP1 signaling axis in tumorigenesis, and provides a rationale for targeting Snail to improve mTOR-targeted therapies.

AKT inhibition overcomes rapamycin resistance by enhancing the repressive function of PRAS40 on mTORC1/4E-BP1 axis.

The mTORC1 inhibitors, rapamycin and its analogs, are known to show only modest antitumor activity in clinic, but the underlying mechanisms remain largely elusive. Here, we found that activated AKT signaling is associated with rapamycin resistance in breast and colon cancers by sustained phosphorylation of the translational repressor 4E-BP1. Treatment of tumor cells with rapamycin or the AKT inhibitor MK2206 showed a limited activity in inhibiting 4E-BP1 phosphorylation, cap-dependent translation, cell growth and motility. However, treatment with both drugs resulted in profound effects in vitro and in vivo. Mechanistic investigation demonstrated that the combination treatment was required to effectively inhibit PRAS40 phosphorylation on both Ser183 and Thr246 mediated by mTORC1 and AKT respectively, and with the combined treatment, dephosphorylated PRAS40 binding to the raptor/mTOR complex was enhanced, leading to dramatic repression of mTORC1-regulated 4E-BP1 phosphorylation and translation. Knockdown of PRAS40 or 4E-BP1 expression markedly reduced the dependence of tumor cells on AKT/mTORC1 signaling for translation and survival. Together, these findings reveal a critical role of PRAS40 as an integrator of mTORC1 and AKT signaling for 4E-BP1-mediated translational regulation of tumor cell growth and motility, and highlight PRAS40 phosphorylation as a potential biomarker to evaluate the therapeutic response to mTOR/AKT inhibitors.