Frequent RNF43 mutation contributes to moderate activation of Wnt signaling in colorectal signet-ring cell carcinoma

Dear Editor,Signet-ring cell carcinoma(SRCC)is a rare subtype of colorectal cancer(CRC)characterized histologically by the accumulation of mucins in the cytoplasm and displacement of nuclei to the cellular periphery,accounting for about 1%CRC(Fig.S1A)(Borger et al.,2007).Compare to common subtypes of CRC,such as adenocarcinoma(AC)and mucinous adenocarcinoma(MAC),SRCC is associated with aggressive behaviors and younger age at presentation(Kang et al.,2005;Sung et al.,2008;Nitsche et al.,2013;Hugen et al.,2014;Inamura et al.,2015).A retrospective analysis of CRC patient's data at Fudan University Shanghai Cancer Center(FUSCC)also indicated a worse overall and disease-free survival of SRCC patients(Fig.S1B and S1C,Table S1).

PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism

Background:Abnormal expression of protein tyrosine phosphatases(PTPs)has been reported to be a crucial cause of cancer.As a member of PTPs,protein tyrosine phosphatase receptor type O(PTPRO)has been revealed to play tumor suppressive roles in several cancers,while its roles in colorectal cancer(CRC)remains to be elucidated.Hence,we aimed to explore the roles and mechanisms of PTPRO in CRC initiation and progression.Methods:The influences of PTPRO on the growth and liver metastasis of CRC cells and the expression patterns of different lipid metabolism enzymes were evaluated in vitro and in vivo.Molecular and biological experiments were conducted to uncover the underpinning mechanisms of dysregulated de novo lipogenesis and fatty acidβ-oxidation.Results:PTPRO expression was notably downregulated in CRC liver metastasis compared to the primary cancer,and such a downregulation was associated with poor prognosis of patients with CRC.PTPRO silencing significantly promoted cell growth and liver metastasis.Compared with PTPRO wild-type mice,PTPROknockout mice developed more tumors and harbored larger tumor loads under treatment with azoxymethane and dextran sulfate sodium.Gene set enrichment analysis revealed that PTPRO downregulation was significantly associated with the fatty acid metabolism pathways.Blockage of fatty acid synthesis abrogated the effects of PTPRO silencing on cell growth and liver metastasis.Further experiments indicated that PTPRO silencing induced the activation of the AKT serine/threonine kinase(AKT)/mammalian target of rapamycin(mTOR)signaling axis,thus promoting de novo lipogenesis by enhancing the expression of sterol regulatory element-binding protein 1(SREBP1)and its target lipogenic enzyme acetyl-CoA carboxylase alpha(ACC1)by activating the AKT/mTOR signaling pathway.Furthermore,PTPRO attenuation decreased the fatty acid oxidation rate by repressing the expression of peroxisome proliferator-activated receptor alpha(PPARα)and its downstream enzyme peroxisomal acyl-coenzyme A oxidase 1(ACOX1)via activating the p38/extracellular signal-regulated kinase(ERK)mitogen-activated protein kinase(MAPK)signaling pathway.Conclusions:PTPRO could suppress CRC development and metastasis via modulating the AKT/mTOR/SREBP1/ACC1 and MAPK/PPARα/ACOX1 pathways and reprogramming lipid metabolism.

GLUT3 induced by AMPK/CREB1 axis is key for withstanding energy stress and augments the efficacy of current colorectal cancer therapies

Cancer cells are usually characterized by hyperactive glucose metabolism,which can often lead to glucose scarcity;thus,alternative pathways to rewire cancer metabolism are required.Here,we demonstrated that GLUT3 was highly expressed in colorectal cancer(CRC)and negatively linked to CRC patient outcomes,whereas GLUT1 was not associated with CRC prognosis.Under glucoselimiting conditions,GLUT3 expedited CRC cell growth by accelerating glucose input and fuelling nucleotide synthesis.Notably,GLUT3 had a greater impact on cell growth than GLUT1 under glucose-limiting stress.Mechanistically,low-glucose stress dramatically upregulated GLUT3 via the AMPK/CREB1 pathway.Furthermore,high GLUT3 expression remarkably increased the sensitivity of CRC cells to treatment with vitamin C and vitamin C-containing regimens.Together,the results of this study highlight the importance of the AMPK/CREB1/GLUT3 pathway for CRC cells to withstand glucose-limiting stress and underscore the therapeutic potential of vitamin C in CRC with high GLUT3 expression.

Effect of niobium content on irradiation microstructure and hardening in FeCrAl-based alloys

Iron-chromium-aluminum(FeCrAl)alloys with different content of niobium(Nb)—0,0.4 wt%,0.8 wt%,and 1.2 wt%—were designed and prepared.All samples were then irradiated with 2.4 MeV Fe^(2+)ion to the dose of 1 and 15 displacements per atom(dpa)at 400℃.The formations of dislocation loops induced by self-ion irradiation in these alloys were investigated by transmission electron microscopy(TEM).Nano-indentation tests were used to assess the hardness and irradiation hardening of samples.For the samples before irradiation,the(Fe,Cr)_(2)(Nb,Mo)Laves phases density and the nano-indentation hardness increased with increasing Nb content of the samples.After irradiation to 1 and 15 dpa,both of a/2<111>and a<100>dislocation loops were produced but no voids orα’phase were found in all samples.With increasing Nb content of the samples,the size of dislocation loops increased first and then decreased,while the total volume number density decreased and then increased.The fraction of a<100>dislocation loops increased first and then decreased with increasing Nb content,and increased with increasing irradiation dose.Dislocation networks and the amorphization of the Laves phases were observed in the samples with irradiation dose of 15 dpa.Irradiation hardening of Nb free samples was two to four times that of Nb containing samples,and the irradiation hardening increased with increasing Nb content of Nb containing samples.The experimental results indicate that the increase of Nb content in Fe Cr Al alloys can increase the density of Laves phases,leading to the decrease of Mo content and increase of Cr content in the matrix.The competition between the two types of solutes affects the nucleation and growth of the dislocation loops.