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KAI1/CD82 is a member of the transmembrane 4 superfamily, which was first identified as a metastasis suppressor for prostate cancer. The expression of KAI1 was found to be reduced in many types of cancers, including prostate, breast, ovarian, cervical and endometrial cancer. However, the role of KAI1 in melanoma pathogenesis is not known. In this study, we investigated the expression level of KAI1 in a large set of melanocytic lesions at different stages. We found that the expression of KAI1 is significantly decreased during melanoma progression. In fact, KAI1 expression is drastically reduced in primary melanoma compared with dysplastic nevi (P = 1.8×10–4) and further reduced in metastatic melanoma compared with primary melanoma (P = 9.4 × 10–15). Furthermore, decreased KAI1 staining is strongly correlated with a worse 5 year and 10 year patient survival. Multivariate Cox regression analysis showed that KAI1 is also an independent prognostic factor for both 5 year and 10 year survival. Moreover, we found that overexpression of KAI1 significantly inhibited melanoma cell migration through suppression of Rho-associated kinase-mediated formation of stress fiber. Our data also suggested that overexpression of KAI1 significantly inhibited melanoma cell invasion by reducing the activity of metalloproteinase-2. In addition, we found that suppression of melanoma cell migration by KAI1 is mediated by another tumor-suppressor protein called inhibitor of growth 4 through the regulation of p65. Taken together, our data suggest that KAI1 may be used as a promising prognostic marker and a possible therapeutic target for human melanoma. [ABSTRACT FROM AUTHOR]

The E3 ubiquitin ligase Fbw7 (F-box and WD repeat domain-containing 7) is broadly considered as a tumor suppressor because of its role in the turnover of several well-known oncoproteins. However, the role of Fbw7 in melanomagenesis is not clear. To investigate the expression profile and biological functions of Fbw7 in melanoma, we examined Fbw7 expression level using melanoma tissue microarray and immunohistochemistry. Our data showed that Fbw7 expression is significantly reduced in primary melanoma compared with dysplastic nevi (P=0.020) and further reduced in metastatic melanoma compared with primary melanoma (P=0.011). Furthermore, we observed a strong correlation between negative Fbw7 expression and a worse 5-year survival of melanoma patients (P=0.015). We also found that both Fbw7 protein and mRNA expression was significantly reduced in nine melanoma cell lines compared with normal melanocytes. Moreover, our in vitro studies showed a remarkable increase of cell migration and stress fiber formation in Fbw7 knockdown cells, and treatment of selective MEK (MAPK/ERK kinase) inhibitor abrogated Fbw7α knockdown-induced melanoma cell migration. Taken together, our findings indicate that Fbw7 has an important role in melanoma progression, and it inhibits melanoma cell migration through the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway and may serve as a prognostic marker. [ABSTRACT FROM AUTHOR]

The tumor suppressor Tip60 regulates gene transcription, DNA damage response, apoptosis, and cancer development, but its role in melanoma is unknown. In this study, we investigated the expression pattern of Tip60 in melanoma and assessed its prognostic value. Using tissue microarrays consisting of 448 cases of melanomas (201 for the training set and 247 for the validation set) and 105 cases of nevi, we found that Tip60 expression was significantly reduced in metastatic melanoma compared to common nevi (P=0.045), dysplastic nevi (P=0.047), and primary melanoma (P=0.001). Kaplan-Meier survival curve and univariate Cox regression analyses showed that reduced Tip60 expression was associated with a poorer 5-year disease-specific survival in primary melanoma (P=0.016) and metastatic melanoma patients (P=0.027). Multivariate Cox regression analyses indicated that Tip60 expression was an independent prognostic marker for primary (P=0.024) and metastatic melanomas (P=0.035). In vitro wound healing assay showed that enforced Tip60 expression inhibited but Tip60 knockdown enhanced melanoma cell migration, suggesting that Tip60 might regulate melanoma metastasis. Finally, we showed that overexpression of Tip60 in melanoma cells resulted in significantly increased chemosensitivity. Our data indicate that Tip60 may serve as a potential biomarker for melanoma patient outcome as well as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Eutectogels are emerging as an appealing soft conductor for self‐powered sensing and the next generation of flexible human–computer interactive devices owing to their inherent mechanical elasticity and high ionic conductivity. However, it still remains a challenge to simultaneously achieve multi‐functional and multi‐response integrations through a facile and sustainable approach. Herein, a self‐healing, environment tolerant, intrinsically conductive, and recyclable eutectogel with multiple responses is developed via one‐step solar‐initiated polymerization of deep eutectic solvents (DESs) and ionic liquids (ILs). Abundant hydrogen bonds and ion‐dipole interactions impart eutectogels with high mechanical strength (8.8 MPa), ultra‐stretchability (>1100%), strong self‐adhesion (≈12 MPa), recyclability, and autonomously self‐healing ability. Furthermore, the intrinsically conductive eutectogels with appealing versatile sensations on strain, temperature, and humidity can serve as wearable sensors for wireless motion recognition and human–computer interaction control. More importantly, the eutectogel‐assembled single‐electrode triboelectric nanogenerator (TENG) exhibits extreme environment‐tolerant and fast self‐healable properties that contribute to maintaining excellent and stable electrical outputs in a wide work temperature range (approximately −40–60 °C), which appear to be promising in self‐powered flexible electronics with high environmental adaptability. [ABSTRACT FROM AUTHOR]

eIF3, whose subunits are frequently overexpressed in cancer, regulates mRNA translation from initiation to termination, but mRNA‐selective functions of individual subunits remain poorly defined. Using multiomic profiling upon acute depletion of eIF3 subunits, we observed that while eIF3a, b, e, and f markedly differed in their impact on eIF3 holo‐complex formation and translation, they were each required for cancer cell proliferation and tumor growth. Remarkably, eIF3k showed the opposite pattern with depletion promoting global translation, cell proliferation, tumor growth, and stress resistance through repressing the synthesis of ribosomal proteins, especially RPS15A. Whereas ectopic expression of RPS15A mimicked the anabolic effects of eIF3k depletion, disruption of eIF3 binding to the 5′‐UTR of RSP15A mRNA negated them. eIF3k and eIF3l are selectively downregulated in response to endoplasmic reticulum and oxidative stress. Supported by mathematical modeling, our data uncover eIF3k‐l as a mRNA‐specific module which, through controlling RPS15A translation, serves as a rheostat of ribosome content, possibly to secure spare translational capacity that can be mobilized during stress. Are there mRNA‐selective functions of individual eIF3 subunits? Here, multiomic profiling upon acute depletion of eIF3 subunits uncovers eIF3k‐l as an mRNA‐specific module that serves as a rheostat of ribosome content, securing spare translational capacity that can be mobilized during stress. Acute depletion of eIF3 subunits has subunit‐selective impact on holo‐eIF3 architecture.eIF3k depletion uniquely causes increased tumor growth and ribosome content.eIF3k depletion boosts the translation of RPS15A mRNA through an eIF3‐binding site in the 5′‐UTR.eIF3k and eIF3l are selectively downregulated by cellular stress, thus promoting cell survival. [ABSTRACT FROM AUTHOR]

Background And Objective:Two recent genome-wide association studies have identified a shared susceptibility variation PLCE1 rs2274223 for esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinomas (GCA). Subsequent case-control studies have reported this association in other populations. However, the findings were controversial and the effect remains undetermined. Our aim is to provide a precise quantification of the association between PLCE1 rs2274223 variation and the risk of ESCC and GCA. Methods:Studies were identified by a literature search in MEDLINE and EMBASE databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association in allele, dominant, recessive, homozygous, and heterozygous models. Results:Ten articles were identified, including 22156 ESCC cases and 28803 controls, 5197 GCA cases and 17613 controls. Overall, PLCE1 rs2274223 G allele (G vs. A: OR=1.26, 95% CI: 1.15-1.39 for ESCC; OR=1.51, 95% CI: 1.35–1.69 for GCA) and its carrier (GG +AG vs. AA: OR = 1.23; 95% CI =1.02-1.49 for ESCC; OR =1.62; 95% CI =1.15-2.29 for GCA) were significantly associated with the risk of ESCC and GCA. In stratified analysis by ethnicity, significant association of PLCE1 rs2274223 G allele and the risk of ESCC (OR=1.33, 95% CI 1.21–1.45) and GCA (OR =1.56, 95% CI: 1.47-1.64) was observed in Chinese population. Conclusions:Our meta-analysis results indicated that PLCE1 rs2274223 G allele significantly contributed to the risk of ESCC and GCA, especially in Chinese population. [ABSTRACT FROM AUTHOR]

The tetraspan protein KAI1 ( CD82) has been previously shown to have important roles in cell migration, invasion, and melanoma prognosis. In this study, we investigated the role of KAI1 regarding melanoma angiogenesis. KAI1 overexpression strongly suppressed the growth of the human umbilical vein endothelial cells and their tubular structure formation in vitro. Also, KAI1 was able to inhibit both interleukin-6 ( IL-6) and VEGF at mRNA and protein levels. Using nude mice in the in vivo study, we showed that KAI1, through the regulation of ING4, inhibited blood vessel formation in matrigel plugs along with the downregulation of IL-6 and VEGF, and the recruitment of CD31-positive cells. Finally, we found that KAI1 was able to suppress the activity of a serine/threonine kinase Akt by suppressing Akt phosphorylation (Ser473). Taken together, our results suggested that KAI1 was able to suppress melanoma angiogenesis by downregulating IL-6 and VEGF expression, and the restoration of KAI1 functionality offered a new approach in human melanoma treatment. [ABSTRACT FROM AUTHOR]

Background: Genomic instability due to UV radiation is one of the leading causes for melanoma. Histone acetyltransferase p300 plays an indispensible role in DNA repair and maintenance of genomic integrity. The present study was performed to analyze the correlation between p300 expression, melanoma progression and patient survival. Methods: Tissue microarray and immunohistochemical analysis was employed to study the expression of p300 in melanoma patients. A total of 358 melanoma patients (250 primary melanoma and 108 metastatic melanoma) were used for the study. Kaplan-Meier, univariate and multivariate Cox regression analysis, and receiver-operating characteristic curves, were used to elucidate the prognostic significance of p300 expression. Results: Our results demonstrate that p300 is expressed in both nucleus and cytoplasm but the nuclear expression of p300 is predominant. The progression of disease from dysplastic nevi to primary melanoma and to metastatic melanoma was associated with decreased nuclear and increased cytoplasmic p300 expression. Especially, the loss of nuclear and gain in cytoplasmic p300 was correlated with the progression of melanoma from AJCC stage II to stage III, which requires the migration and metastasis of cancer cells from primary sites to lymph nodes. Similarly, decrease in nuclear, and increase in cytoplasmic p300 expression correlated with worse survival of melanoma patients. Nuclear p300 but not cytoplasmic p300 could predict the patient survival independent of AJCC stage, age and gender. Conclusion: Loss of nuclear p300 expression is an indicator of worse patient survival and is an independent prognostic marker for melanoma. [ABSTRACT FROM AUTHOR]

Exposure to heat stress triggers a well‐defined acute response marked by HSF1‐dependent transcriptional upregulation of heat shock proteins. Cells allowed to recover acquire thermotolerance, but this adaptation is poorly understood. By quantitative proteomics, we discovered selective upregulation of HSP70‐family chaperone HSPA1 and its co‐factors, HSPH1 and DNAJB1, in MCF7 breast cancer cells acquiring thermotolerance. HSPA1 was found to have dual function during heat stress response: (i) During acute stress, it promotes the recruitment of the 26S proteasome to translating ribosomes, thus poising cells for rapid protein degradation and resumption of protein synthesis upon recovery; (ii) during thermotolerance, HSPA1 together with HSPH1 maintains ubiquitylated nascent/newly synthesized proteins in a soluble state required for their efficient proteasomal clearance. Consistently, deletion of HSPH1 impedes thermotolerance and esophageal tumor growth in mice, thus providing a potential explanation for the poor prognosis of digestive tract cancers with high HSPH1 and nominating HSPH1 as a cancer drug target. We propose dual roles of HSPA1 either alone or in complex with HSPH1 and DNAJB1 in promoting quality control of nascent/newly synthesized proteins and cellular thermotolerance. Synopsis: How cells exposed to heat stress acquire thermotolerance is poorly understood. Here, quantitative proteomics identifies upregulation of HSP70‐family chaperone HSPA1, which fulfills dual function in quality control of nascent proteins at translating ribosomes. Proteotoxic stress causes translation arrest, ubiquitylation of nascent/newly synthesized proteins, and proteasome recruitment to ribosomes.Proteasome recruitment to ribosomes is augmented by HSP70 activity independently of nascent chain ubiquitylation.HSPA1 in complex with HSPH1‐DNAJB1 cofactors maintains solubility and proteasomal clearance of ubiquitylated proteins.Low HSPH1 expression impedes nascent‐protein quality control and tumor growth, correlating with favorable outcome. [ABSTRACT FROM AUTHOR]

Holographic data storage system is a candidate for the information recording due to its large storage capacity and high transfer rate. We propose an unequally spaced four levels phase encoding in the holographic data storage system here. Compared with two levels or three levels phase encoding, four levels phase encoding effectively improves the code rate. While more phase levels can further improve code rate, it also puts higher demand for the camera to differentiate the resulting smaller grayscale difference. Unequally spaced quaternary level phases eliminates the ambiguity of pixels with same phase difference relative to reference light compared to equally spaced quaternary levels. Corresponding encoding pattern design with phase pairs as the data element and decoding method were developed. Our encoding improves the code rate up to 0.875, which is 1.75 times of the conventional amplitude method with an error rate of 0.13 % according to our simulation results. [ABSTRACT FROM AUTHOR]

[Display omitted] • The free-standing, monolithic and anisotropic graphite networks were constructed by a two-stage, economy, facile expansion process. • The sensitivity of the sensors/switches can be accurately tailored. • The wireless monitoring of human movement was realized by integrating the sensors/switches with microelectronic components. Highly sensitive strain sensors and switches are essential components to wearable electronics in many emerging applications such as personal health monitoring, human–machine interaction, smart robots and intelligent control system. Herein, we report a new highly-anisotropic graphite framework (HAGF) for creating strain sensors and switches with high flexibility, stretchability and sensitivity. The highly anisotropic three-dimensional (3D) graphite structure was fabricated via a facile, low-cost and scalable expansion of commercially-available graphite papers. By controlling the orientation structure and thickness of HAGF, the contact area and switchable conduction path can be tailored to create strain sensors and switches based on HAGF/PDMS composites to achieve a tunable gauge factor between 1.3 and 379, an ultra-high ON/OFF ratio in the order of 1035 with tunable critical switching strain (8 % ∼ 50 %), an excellent long-term repeatability of over 1000 cycles at a peak strain of 50 %, and a stretchability up to 100 %. The potentials of the new sensors and switches are demonstrated by pairing them with the smartphone for tracking and recognition of human motions, offering a new solution to a wide range of portable devices and mobile applications. [ABSTRACT FROM AUTHOR]

Melanoma is the deadliest cutaneous malignancy because of its high incidence of metastasis. Melanoma growth and metastasis relies on sustained angiogenesis; therefore, inhibiting angiogenesis is a promising approach to treat metastatic melanoma. JWA is a novel microtubule-associated protein and our previous work revealed that JWA inhibited melanoma cell invasion and metastasis. However, the role of JWA in melanoma angiogenesis and the prognostic value are still unknown. Here, we report that JWA in melanoma cells significantly inhibited the tube formation of endothelial cells. In addition, JWA regulated integrin-linked kinase (ILK) through integrin αVβ3 and such regulation was achieved through the transcription factor Sp1. Notably, both in vitro and in vivo angiogenesis assays revealed that JWA dramatically suppressed melanoma angiogenesis by inhibiting ILK signaling. Furthermore, we examined the expression of JWA protein in a large set of melanocytic lesions (n = 505) at different stages by tissue microarray and found an inverse correlation between JWA expression and melanoma progression (P = 5 × 10–6). Importantly, reduced JWA expression was correlated with a poorer overall, and disease-specific 5 year survival of patients (P = 0.001 and 0.007, respectively). Multivariate Cox regression analyses indicated that JWA was an independent prognostic marker for melanoma patients. Moreover, we found a significant negative correlation between JWA and ILK in melanoma biopsies, and their concomitant expression was closely correlated with melanoma patient survival (P = 0.004), further indicating the regulation of ILK expression by JWA is critical in melanoma. Taken together, our data highlight the function of JWA in melanoma angiogenesis and reveal the clinical prognostic value of JWA.This study investigated the function of JWA in melanoma angiogenesis and its prognostic value in melanoma patients. It revealed that JWA inhibits melanoma angiogenesis by suppressing ILK signaling and may serve as a prognostic biomarker for melanoma. [ABSTRACT FROM AUTHOR]

SMIP004-7 is a small molecule inhibitor of mitochondrial respiration with selective in vivo anti-cancer activity through an as-yet unknown molecular target. We demonstrate here that SMIP004-7 targets drug-resistant cancer cells with stem-like features by inhibiting mitochondrial respiration complex I (NADH:ubiquinone oxidoreductase, complex I [CI]). Instead of affecting the quinone-binding site targeted by most CI inhibitors, SMIP004-7 and its cytochrome P450-dependent activated metabolite(s) have an uncompetitive mechanism of inhibition involving a distinct N-terminal region of catalytic subunit NDUFS2 that leads to rapid disassembly of CI. SMIP004-7 and an improved chemical analog selectively engage NDUFS2 in vivo to inhibit the growth of triple-negative breast cancer transplants, a response mediated at least in part by boosting CD4+ and CD8+ T cell-mediated immune surveillance. Thus, SMIP004-7 defines an emerging class of ubiquinone uncompetitive CI inhibitors for cell autonomous and microenvironmental metabolic targeting of mitochondrial respiration in cancer. [Display omitted] • SMIP004 compounds inhibit NADH:ubiquinone oxidoreductase (complex I) • Unique ubiquinone uncompetitive mechanism of inhibition • In vivo target engagement involves complex I subunit NDUFS2 • Complex I inhibition reverses hypoxia and promotes cancer immune surveillance Mitochondrial complex I is identified as the target of cancer selective cytotoxic agent SMIP004-7. Jain et al. show that anti-tumor activity involves ubiquinone uncompetitive inhibition of complex I, leading to a reversal of tumor hypoxia and promotion of tumor immune surveillance. [ABSTRACT FROM AUTHOR]

eIF3, a multi-subunit complex with numerous functions in canonical translation initiation, is known to interact with 40S and 60S ribosomal proteins and translation elongation factors, but a direct involvement in translation elongation has never been demonstrated. We found that eIF3 deficiency reduced early ribosomal elongation speed between codons 25 and 75 on a set of ∼2,700 mRNAs encoding proteins associated with mitochondrial and membrane functions, resulting in defective synthesis of their encoded proteins. To promote elongation, eIF3 interacts with 80S ribosomes translating the first ∼60 codons and serves to recruit protein quality-control factors, functions required for normal mitochondrial physiology. Accordingly, eIF3e+/− mice accumulate defective mitochondria in skeletal muscle and show a progressive decline in muscle strength. Hence, eIF3 interacts with 80S ribosomes to enhance, at the level of early elongation, the synthesis of proteins with membrane-associated functions, an activity that is critical for mitochondrial physiology and muscle health. • eIF3—via eIF3e—promotes mRNA selective early translation elongation • eIF3e-dependent mRNAs encode membrane, secretory, and organelle targeted proteins • eIF3 travels with 80S ribosomes until nascent chains emerge for subcellular targeting • In vivo , eIF3e promotes mitochondrial function and skeletal muscle health Lin et al. discovered that, in addition to its function in canonical translation initiation, multi-subunit eIF3 migrates with post-initiation 80S ribosomes to promote early translation elongation of mRNAs encoding organellar, secretory, and membrane-targeted proteins. Loss of eIF3's elongation and subcellular targeting activity leads to mitochondrial and skeletal muscle dysfunction. [ABSTRACT FROM AUTHOR]

The prolyl isomerase Pin1 is widely over-expressed or over-activated in cancers and promotes tumorigenesis. The authors investigated the expression level of Pin1 and analyzed the prognostic value of Pin1 expression using a large-scale melanoma tissue microarray study. Two independent sets of tissue microarrays were employed, including 114 melanoma cases in the discovery set and 424 in the validation set (538 cases in total), 32 normal nevi and 86 dysplastic nevi 118 cases of nevi. The subcellular Pin1 expression in different stages of melanocytic lesions and its prognostic significance were studied. High expression (IRS 0-8) of cytoplasmic Pin1 was observed in 3.13%, 8.33%, 16.49% and 22.76% of the biopsies in normal nevi, dysplastic nevi, primary melanoma and metastatic melanoma, respectively. Significant differences for cytoplasmic Pin1 staining were observed between normal nevi and metastatic melanoma (P = 0.011, χ2 test), between dysplastic nevi and primary melanoma (P = 0.046, χ2 test) and between dysplastic nevi and metastatic melanoma (P = 0.016, χ2 test). Kaplan-Meier survival analysis showed that increased cytoplasmic Pin1 expression was associated with a worse 5-year melanoma-specific survival of melanoma (P < 0.001) and metastatic melanoma patients (P = 0.004). Multivariate Cox regression analysis showed that cytoplasmic Pin1 expression is an independent prognostic factor in melanoma. Our data indicate that cytoplasmic Pin1 plays an important role in melanoma pathogenesis and progression, and serve as a potential prognostic marker for melanoma. [ABSTRACT FROM AUTHOR]