A Novel SASH1-IQGAP1-E-Cadherin Signal Cascade Mediates Breast Cancer Metastasis

SAM and SH3 domain-containing protein 1 (SASH1) was previously described as a candidate tumor suppressor gene in breast cancer and colon cancer to mediate tumor metastasis and tumor growth. However, the underlying mechanism that SASH1 implements breast cancer metastasis in most solid cancers remains unexplored. In this study, SASH1 was identified to bind to IQ motif-containing GTPase activating protein 1 (IQGAP1). In breast cancer tissues, there was a correlation between the expressions of SASH1 and IQGAP1 (P  0.05). Therefore, it is suggested that SASH1 may form a new signaling cascade with IQGAP1 and E-cadherin to regulate breast cancer metastasis

Multi-omics profiling reveal responses of three major Dendrobium species from different growth years to medicinal components

Dendrobium is a perennial herb found in Asia that is known for its medicinal and ornamental properties. Studies have shown that the stem is the primary medicinal component of Dendrobium spp. To investigate the effect of the species and age of Dendrobium (in years) on the content of its medicinal components, we collected the stems of 1-to-4-year-old D. officinale, D. moniliforme, and D. huoshanense, sequenced the transcriptome, metabolome, and microbiome, and analyzed the data in a comprehensive multi-omics study. We identified 10,426 differentially expressed genes (DEGs) with 644 differentially accumulated metabolites (DAMs) from 12 comparative groups and mapped the flavonoid pathway based on DEGs and DAMs. Transcriptomic and metabolomic data indicated a general trend of the accumulation of flavonoids exhibiting pharmacological effects in the three Dendrobium species. In addition, joint metabolome and microbiome analyses showed that actinobacteria was closely associated with flavonoid synthesis with increasing age. Our findings provide novel insights into the interactions of flavonoids of Dendrobium with the transcriptome and microbiome

Theoretical Corrections of RDR_D and RD∗R_{D^*}

$R_{D^{(*)}}$ is the ratio of branching ratio $\overline{B} \rightarrow D^{(*)}\tau\overline{\nu}_{\tau}$ to $\overline{B} \rightarrow D^{(*)}l\overline{\nu}_{l}$. There is a gap of $2\sigma_{exp}$ or more between its experimental value and the prediction under the standard model(SM). People extend the MSSM with the local gauge group $U(1)_X$ to obtain the $U(1)_X$SSM. Compared with MSSM, $U(1)_X$SSM has more superfields and effects. In $U(1)_X$SSM, we research the decays $\overline{B} \rightarrow D^{(*)}l\overline{\nu}_{l}$ and calculate $R_{D^{(*)}}$. The obtained numerical results of $R_{D^{(*)}}$ are further corrected under $U(1)_X$SSM, which is much better than the SM predictions. After correction, the theoretical value of $R_{D^{(*)}}$ can reach in one $\sigma_{exp}$ range of the averaged experiment central value

A Novel P53/POMC/Gas/SASH1 Autoregulatory Feedback Loop and Pathologic Hyperpigmentation

P53-regulated proteins in transcriptional level are associated with many signal transduction pathways and p53 plays a pivotal role in a number of positive and negative autoregulatory feedback loops. Although POMC/α-MSH productions induced by ultraviolet (UV) are directly mediated by p53, p53 is related to UV-independent pathological pigmentation. In the process of identifying the causative gene of dyschromatosis universalis hereditaria (DUH), three mutations encoding amino acid substitutions were found in the gene SAM and SH3 domain containing 1 (SASH1). SASH1 was identified to interact with guanine nucleotide-binding protein subunit-alpha isoforms short (Gαs). However, for about 90 years, the pathological gene and the pathological mechanism of DUH are unclear. Our study indicates that SASH1 is physiologically medicated by p53 upon UV stimulation and a reciprocal SASH-p53 inducement is existed physiologically and pathophysiologically. A novel p53/POMC/α-MSH/Gαs/SASH1 signal cascade regulates SASH1 to foster melanogenesis. SASH1 mutations control a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop to promote pathological hyperpigmentation phenotype in DUH-affected individuals. Our work illustrates a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop that is mediated by SASH1 mutations to foster pathological hyperpigmentation phenotype

ISG15 inhibits IFN- a -Resistant liver cancer cell growth

Hepatocellular carcinoma (HCC) is one of the most prevalent tumors worldwide. Interferon-a (IFN-a) has been widely used in the treatment of HCC, but patients eventually develop resistance. ISG15 ubiquitin-like modifier (ISG15) is a ubiquitin-like protein transcriptionally regulated by IFN-a which shows antivirus and antitumor activities. However, the exact role of ISG15 is unknown. In the present study, we showed that IFN-a significantly induced ISG15 expression but failed to induce HepG2 cell apoptosis, whereas transient overexpression of ISG15 dramatically increased HepG2 cell apoptosis. ISG15 overexpression increased overall protein ubiquitination, which was not observed in cells with IFN-a-induced ISG15 expression, suggesting that IFN-a treatment not only induced the expression of ISG15 but also inhibited ISG15-mediated ubiquitination. The tumor suppressor p53 and p21 proteins are the key regulators of cell survival and death in response to stress signals such as DNA damage. We showed that p53 or p21 is only up regulated in HepG2 cells ectopically expressing ISG15, but not in the presence of IFN-a-induced ISG15. Our results suggest that ISG15 overexpression could be developed into a powerful gene-therapeutic tool for treating IFN-a-resistant HCC. © 2013 Xin-xing Wan et al

Identification of miRNAs and their target genes in developing soybean seeds by deep sequencing

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) regulate gene expression by mediating gene silencing at transcriptional and post-transcriptional levels in higher plants. miRNAs and related target genes have been widely studied in model plants such as <it>Arabidopsis </it>and rice; however, the number of identified miRNAs in soybean (<it>Glycine max</it>) is limited, and global identification of the related miRNA targets has not been reported in previous research.</p> <p>Results</p> <p>In our study, a small RNA library and a degradome library were constructed from developing soybean seeds for deep sequencing. We identified 26 new miRNAs in soybean by bioinformatic analysis and further confirmed their expression by stem-loop RT-PCR. The miRNA star sequences of 38 known miRNAs and 8 new miRNAs were also discovered, providing additional evidence for the existence of miRNAs. Through degradome sequencing, 145 and 25 genes were identified as targets of annotated miRNAs and new miRNAs, respectively. GO analysis indicated that many of the identified miRNA targets may function in soybean seed development. Additionally, a soybean homolog of Arabidopsis SUPPRESSOR OF GENE SLIENCING 3 (<it>AtSGS3</it>) was detected as a target of the newly identified miRNA Soy_25, suggesting the presence of feedback control of miRNA biogenesis.</p> <p>Conclusions</p> <p>We have identified large numbers of miRNAs and their related target genes through deep sequencing of a small RNA library and a degradome library. Our study provides more information about the regulatory network of miRNAs in soybean and advances our understanding of miRNA functions during seed development.</p

Arabidopsis blue light receptor phototropin 1 undergoes blue light-induced activation in membrane microdomains

Phototropin (phot)-mediated signaling initiated by blue light (BL) plays a critical role in optimizing photosynthetic light capture at the plasma membrane (PM) in plants. However, the mechanisms underlying the regulation of phot activity at the PM in response to BL remain largely unclear. In this study, by single-particle tracking and step-wise photobleaching analysis we demonstrated that in the dark phot1-GFP proteins remain in an inactive state and mostly present as a monomer. The phot1-GFP diffusion rate and its dimerization increased in a dose-dependent manner in response to BL. In contrast, BL did not affect the lateral diffusion of kinase-inactive phot1 -GFP, whereas it did enhance its dimerization, suggesting that phot1 dimerization is independent of its phosphorylation. Förster resonance energy transfer-fluorescence lifetime imaging microscopy (FRET-FLIM) analysis revealed that the interaction between phot1-GFP and AtRem1.3-mCherry was enhanced along with increased time of BL treatment. However, the BL-dependent interaction was not obvious in plants co-expressing phot1 -GFP and AtRem1.3-mCherry, implicating that BL facilitated the translocation of functional phot1-GFP into AtRem1.3-labeled microdomains to activate phot-mediated signaling. Conversely, sterol depletion attenuated phot1-GFP dynamics, dimerization, and phosphorylation. Taken together, these results indicate that membrane microdomains act as an organizing platform essential for proper function of activated phot1 at the PM

The paradoxical patterns of expression of indoleamine 2,3-dioxygenase in colon cancer

<p>Abstract</p> <p>Background</p> <p>One of the putative mechanisms of tumor immune escape is based on the hypothesis that carcinomas actively create an immunosuppressed state via the expression of indoleamine 2,3-dioxygenase (IDO), both in the cancer cells and in the immune cells among the tumor-draining lymph nodes (TDLN). In an attempt to verify this hypothesis, the patterns of expression of IDO in the cancer cells and the immune cells among colon cancers were examined.</p> <p>Methods</p> <p>Seventy-one cases of pathologically-confirmed colon cancer tissues matched with adjacent non-cancerous tissues, lymph node metastases, and TDLN without metastases were collected at the Sun Yat-sen Cancer Center between January 2000 and December 2000. The expression of IDO and Bin1, an IDO regulator, was determined with an immunohistochemical assay. The association between IDO or Bin1 expression and TNM stages and the 5-year survival rate in colon cancer patients was analyzed.</p> <p>Results</p> <p>IDO and Bin1 were detected in the cytoplasm of cancer cells and normal epithelium. In primary colon cancer, the strong expression of IDO existed in 9/71 cases (12.7%), while the strong expression of Bin1 existed in 33/71 cases (46.5%). However, similar staining of IDO and Bin1 existed in the adjacent non-cancerous tissues. Among the 41 cases with primary colon tumor and lymph node metastases, decreased expression of IDO was documented in the lymph node metastases. Furthermore, among the TDLN without metastases, a higher density of IDO⁺cells was documented in 21/60 cases (35%). Both univariate and multivariate analyses revealed that the density of IDO⁺cells in TDLN was an independent prognostic factor. The patients with a higher density of IDO⁺cells in TDLN had a lower 5-year survival rate (37.5%) than the cells with a lower density (73.1%).</p> <p>Conclusion</p> <p>This study demonstrated paradoxical patterns of expression of IDO in colon cancer. The high density IDO⁺cells existed in TDLN and IDO was down-regulated in lymph nodes with metastases, implying that IDO in tumor and immune cells functions differently.</p

The density of macrophages in the invasive front is inversely correlated to liver metastasis in colon cancer

<p>Abstract</p> <p>Background</p> <p>Although an abundance of evidence has indicated that tumor-associated macrophages (TAMs) are associated with a favorable prognosis in patients with colon cancer, it is still unknown how TAMs exert a protective effect. This study examined whether TAMs are involved in hepatic metastasis of colon cancer.</p> <p>Materials and methods</p> <p>One hundred and sixty cases of pathologically-confirmed specimens were obtained from colon carcinoma patients with TNM stage IIIB and IV between January 1997 and July 2004 at the Cancer Center of Sun Yat-Sen University. The density of macrophages in the invasive front (CD68TF_Hotspot) was scored with an immunohistochemical assay. The relationship between the CD68TF_Hotspotand the clinicopathologic parameters, the potential of hepatic metastasis, and the 5-year survival rate were analyzed.</p> <p>Results</p> <p>TAMs were associated with the incidence of hepatic metastasis and the 5-year survival rate in patients with colon cancers. Both univariate and multivariate analyses revealed that the CD68TF_Hotspotwas independently prognostic of survival. A higher 5-year survival rate among patients with stage IIIB after radical resection occurred in patients with a higher macrophage infiltration in the invasive front (81.0%) than in those with a lower macrophage infiltration (48.6%). Most importantly, the CD68TF_Hotspotwas associated with both the potential of hepatic metastasis and the interval between colon resection and the occurrence of hepatic metastasis.</p> <p>Conclusion</p> <p>This study showed evidence that TAMs infiltrated in the invasive front are associated with improvement in both hepatic metastasis and overall survival in colon cancer, implying that TAMs have protective potential in colon cancers and might serve as a novel therapeutic target.</p