Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

Overexpressing GH3.1 and GH3.1L reduces susceptibility to Xanthomonas citri subsp. citri by repressing auxin signaling in citrus (Citrus sinensis Osbeck).

The auxin early response gene Gretchen Hagen3 (GH3) plays dual roles in plant development and responses to biotic or abiotic stress. It functions in regulating hormone homeostasis through the conjugation of free auxin to amino acids. In citrus, GH3.1 and GH3.1L play important roles in responding to Xanthomonas citri subsp. citri (Xcc). Here, in Wanjingcheng orange (Citrus sinensis Osbeck), the overexpression of CsGH3.1 and CsGH3.1L caused increased branching and drooping dwarfism, as well as smaller, thinner and upward curling leaves compared with wild-type. Hormone determinations showed that overexpressing CsGH3.1 and CsGH3.1L decreased the free auxin contents and accelerated the Xcc-induced decline of free auxin levels in transgenic plants. A resistance analysis showed that transgenic plants had reduced susceptibility to citrus canker, and a transcriptomic analysis revealed that hormone signal transduction-related pathways were significantly affected by the overexpression of CsGH3.1 and CsGH3.1L. A MapMan analysis further showed that overexpressing either of these two genes significantly downregulated the expression levels of the annotated auxin/indole-3-acetic acid family genes and significantly upregulated biotic stress-related functions and pathways. Salicylic acid, jasmonic acid, abscisic acid, ethylene and zeatin levels in transgenic plants displayed obvious changes compared with wild-type. In particular, the salicylic acid and ethylene levels involved in plant resistance responses markedly increased in transgenic plants. Thus, the overexpression of CsGH3.1 and CsGH3.1L reduces plant susceptibility to citrus canker by repressing auxin signaling and enhancing defense responses. Our study demonstrates auxin homeostasis' potential in engineering disease resistance in citrus

CsBZIP40, a BZIP transcription factor in sweet orange, plays a positive regulatory role in citrus bacterial canker response and tolerance.

Citrus bacterial canker (CBC) caused by Xanthomonas citri subsp. citri (Xcc) is a systemic bacterial disease that affects citrus plantations globally. Biotic stress in plants has been linked to a group of important transcription factors known as Basic Leucine Zippers (BZIPs). In this study, CsBZIP40 was functionally characterized by expression analysis, including induction by Xcc and hormones, subcellular localization, over-expression and RNAi silencing. CsBZIP40 belongs to group D of the CsBZIP family of transcription factors and localizes in the nucleus, potentially serving as a transcriptional regulator. In wild type (WT) plants CsBZIP40 can be induced by plant hormones in addition to infection by Xcc which has given insight into its involvement in CBC. In the present study, over-expression of CsBZIP40 conferred resistance to Xcc while its silencing led to Xcc susceptibility. Both over-expression and RNAi affected salicylic acid (SA) production and expression of the genes involved in the SA synthesis and signaling pathway, in addition to interaction of CsBZIP40 with CsNPR1, as detected by a GST pull-down assay. Taken together, the results of this study confirmed the important role of CsBZIP40 in improving resistance to citrus canker through the SA signaling pathway by the presence of NPR1 to activate PR genes. Our findings are of potential value in the breeding of tolerance to CBC in citrus fruits

Systematic Analysis and Functional Validation of Citrus Pectin Acetylesterases (CsPAEs) Reveals that CsPAE2 Negatively Regulates Citrus Bacterial Canker Development

The present study was designed to serve as a comprehensive analysis of Citrus sinensis (C. sinensis) pectin acetylesterases (CsPAEs), and to assess the roles of these PAEs involved in the development of citrus bacterial canker (CBC) caused by Xanthomonas citri subsp. citri (Xcc) infection. A total of six CsPAEs were identified in the genome of C. sinensis, with these genes being unevenly distributed across chromosomes 3, 6, and 9, and the unassembled scaffolds. A subset of CsPAEs were found to be involved in responses to Xcc infection. In particular, CsPAE2 was identified to be associated with such infections, as it was upregulated in CBC-susceptible variety Wanjincheng and inversely in CBC-resistant variety Calamondin. Transgenic citrus plants overexpressing CsPAE2 were found to be more susceptible to CBC, whereas the silencing of this gene was sufficient to confer CBC resistance. Together, these findings provide evolutionary insights into and functional information about the CsPAE family. This study also suggests that CsPAE2 is a potential candidate gene that negatively contributes to bacterial canker disease and can be used to breed CBC-resistant citrus plants

Proteomic and metabolomic analyses provide insight into the off-flavour of fruits from citrus trees infected with ‘Candidatus Liberibacter asiaticus’

Pathogenic profiling: why fruit from bacteria-infected trees tastes bad The bacteria Candidatus Liberibacter asiaticus (CaLas) causes orange trees to produce poor-tasting fruit thanks to the decreased production of flavour-enhancing proteins, sugars, and metabolites. The University of Florida’s Frederick Gmitter and his team of US and Chinese scientists profiled the proteins and metabolites of healthy Valencia sweet orange trees infected with CaLas, a bacterial pathogen that causes the citrus disease Huanglongbing and reduces the quantity and quality of fruit and juice. The researchers found 123 differentially-expressed proteins and decreased numbers of taste-enhancing constituents, including those mediated by key energy-producing processes. This degradation involved a class of chemicals called terpenoids, which the authors link to poor quality fruit. These results provide insights into the pathogenesis of CaLas infection and could empower future studies to prevent the impact of the bacteria and Huanglongbing infection

Comparative iTRAQ proteomic profiling of sweet orange fruit on sensitive and tolerant rootstocks infected by 'Candidatus Liberibacter asiaticus'.

Citrus Huanglongbing (HLB), which is also known as citrus greening, is a destructive disease continuing to devastate citrus production worldwide. Although all citrus varieties can be infected with 'Candidatus Liberibacter asiaticus' (CaLas), a certain level of HLB tolerance of scion varieties can be conferred by some rootstocks. To understand the effects of rootstock varieties on orange fruit under CaLas stress, comparative iTRAQ proteomic profilings were conducted, using fruit from 'Valencia' sweet orange grafted on the sensitive ('Swingle') and tolerant rootstocks (a new selection called '46x20-04-48') infected by CaLas as experimental groups, and the same plant materials without CaLas infection as controls. The symptomatic fruit on 'Swingle' had 573 differentially-expressed (DE) proteins in comparison with their healthy fruit on the same rootstock, whereas the symptomatic fruit on '46x20-04-48' had 263 DE proteins. Many defense-associated proteins were down-regulated in the symptomatic fruit on 'Swingle' rootstock that were seldom detected in the symptomatic fruit on the '46x20-04-48' rootstock, especially the proteins involved in the jasmonate biosynthesis (AOC4), jasmonate signaling (ASK2, RUB1, SKP1, HSP70T-2, and HSP90.1), protein hydrolysis (RPN8A and RPT2a), and vesicle trafficking (SNAREs and Clathrin) pathways. Therefore, we predict that the down-regulated proteins involved in the jasmonate signaling pathway and vesicle trafficking are likely to be related to citrus sensitivity to the CaLas pathogen

Additional file 1 of High expression of TBRG4 in relation to unfavorable outcome and cell ferroptosis in hepatocellular carcinoma

Additional file 1: Supplemental Fig. 1. Validation of TBRG4 in ICGC cohort and migration experiment. Supplemental Fig. 2. Original image of western blot experiment