Transmembrane proteins (TMEMs) constitute a large family of proteins that span biological membranes and are distributed across various cellular organelles, playing key roles in maintaining cellular homeostasis. Increasing evidence has revealed that dysregulation of TMEMs is closely associated with cancer development and progression. Therefore, a deeper understanding of the relationship between TMEMs and cancer is essential. Different TMEMs can function either as oncogenes or tumour suppressors, depending on the context. In this review, we explore the involvement of TMEMs in cancer, categorizing them into three groups based on their roles: oncogenic, tumour-suppressive or dual-function (both oncogenic and tumour-suppressive). We summarize the roles of various TMEMs in different cancer types, highlighting both well-characterized proteins and those identified through database screening, even if their exact molecular mechanisms remain unclear. Where possible, we include known signalling pathways associated with these TMEMs. This review highlights the critical roles of the TMEM protein family and encourages further research into their mechanisms, prognostic value and potential as targets for cancer therapy.

Areca nut (AN) is used for traditional herbal medicine and social activities in several countries. It was used as early as about A.D. 25-220 as a remedy. Traditionally, AN was applied for several medicinal functions. However, it was also reported to have toxicological effects. In this review article, we updated recent trends of research in addition to acquire new knowledge about AN. First, the history of AN usage from ancient years was described. Then, the chemical components of AN and their biological functions was compared; arecoline is an especially important compound in AN. AN extract has different effects caused by different components. Thus, the dual effects of AN with pharmacological and toxicological effects were summarized. Finally, we described perspectives, trends and challenges of AN. It will provide the insight of removing or modifying the toxic compounds of AN extractions for enhancing their pharmacological activity to treat several diseases in future applications.

Colon cancer is the third most important cancer type, leading to a remarkable number of deaths, indicating the necessity of new biomarkers and therapeutic targets for colon cancer patients. Several transmembrane proteins (TMEMs) are associated with tumor progression and cancer malignancy. However, the clinical significance and biological roles of TMEM211 in cancer, especially in colon cancer, are still unknown. In this study, we found that TMEM211 was highly expressed in tumor tissues and the increased TMEM211 was associated with poor prognosis in colon cancer patients from The Cancer Genome Atlas (TCGA) database. We also showed that abilities regarding migration and invasion were reduced in TMEM211-silenced colon cancer cells (HCT116 and DLD-1). Moreover, TMEM211-silenced colon cancer cells showed decreased levels of Twist1, N-cadherin, Snail and Slug but increased levels of E-cadherin. Levels of phosphorylated ERK, AKT and RelA (NF-κB p65) were also decreased in TMEM211-silenced colon cancer cells. Our findings indicate that TMEM211 regulates epithelial–mesenchymal transition for metastasis through coactivating the ERK, AKT and NF-κB signaling pathways, which might provide a potential prognostic biomarker or therapeutic target for colon cancer patients in the future.

Arecoline is known to induce reactive oxygen species (ROS). Our previous studies showed that arecoline inhibited myogenic differentiation and acetylcholine receptor cluster formation of C2C12 myoblasts. N-acetyl-cysteine (NAC) is a known ROS scavenger. We hypothesize that NAC scavenges the excess ROS caused by arecoline. In this article we examined the effect of NAC on the inhibited myoblast differentiation by arecoline and related mechanisms. We found that NAC less than 2 mM is non-cytotoxic to C2C12 by viability analysis. We further demonstrated that NAC attenuated the decreased number of myotubes and nuclei in each myotube compared to arecoline treatment by H & E staining. We also showed that NAC prevented the decreased expression level of the myogenic markers, myogenin and MYH caused by arecoline, using immunocytochemistry and western blotting. Finally, we found that NAC restored the decreased expression level of p-ERK1/2 by arecoline. In conclusion, our results indicate that NAC attenuates the damage of the arecoline-inhibited C2C12 myoblast differentiation by the activation/phosphorylation of ERK. This is the first report to demonstrate that NAC has beneficial effects on skeletal muscle myogenesis through ERK1/2 upon arecoline treatment. Since defects of skeletal muscle associates with several diseases, NAC can be a potent drug candidate in diseases related to defects in skeletal muscle myogenesis.

Lymph node (LN) metastasis causes poor prognosis for patients with prostate cancer (PCa). Although LN-cells and cellular responses play a pivotal role in cancer metastasis, the interplay between LN-cells and PCa cells is undetermined due to the small size and widespread distribution of LNs. To identify factors responsible for LN metastasis, a 3D cell culture biosystem is fabricated to simulate LN responses during metastasis. First, it is determined that LN explants previously exposed to high metastatic PCa release substantially more chemotactic factors to promote metastatic PCa migration than those exposed to low-metastatic PCa. Furthermore, T-lymphocytes are found to produce chemotactic factors in LNs, among which, CXCL12, CCL21, and IL-10 are identified to have the most chemotactic effect. To mimic the LN microenvironment, Cytodex beads are seeded with T cells to produce a LN-mimetic biosystem in both static and flow conditions. As expected, the flow condition permits prolonged cellular responses. Interestingly, when PCa cells with varying metastatic potentials are introduced into the system, it produces PCa-specific chemokines accordingly. These results support that the LN mimetic helps in analyzing the processes underlying metastasized LNs and for testing various treatments to reduce cancer LN metastasis.

Biotechnology and BioengineeringVolume 116, Issue 2 p. 235-238 ISSUE INFORMATIONFree Access Biotechnology and Bioengineering: Volume 116, Number 2, February 2019 First published: 07 January 2019 https://doi.org/10.1002/bit.26751AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Volume116, Issue2February 2019Pages 235-238 RelatedInformation

Heterogeneous ribonucleoprotein A1 (hnRNP A1) is crucial for regulating alternative splicing. Its integrated function within an organism has not, however, been identified. We generated hnRNP A1 knockout mice to study the role of hnRNP A1 in vivo. The knockout mice, hnRNP A1−/−, showed embryonic lethality because of muscle developmental defects. The blood pressure and heart rate of the heterozygous mice were higher than those of the wild-type mice, indicating heart function defects. We performed mouse exon arrays to study the muscle development mechanism. The processes regulated by hnRNP A1 included cell adhesion and muscle contraction. The expression levels of muscle development-related genes in hnRNP A1+/− mice were significantly different from those in wild-type mice, as detected using qRT-PCR. We further confirmed the alternative splicing patterns of muscle development-related genes including mef2c, lrrfip1, usp28 and abcc9. Alternative mRNA isoforms of these genes were increased in hnRNP A1+/− mice compared with wild-type mice. Furthermore, we revealed that the functionally similar hnRNP A2/B1 did not compensate for the expression of hnRNP A1 in organisms. In summary, our study demonstrated that hnRNP A1 plays a critical and irreplaceable role in embryonic muscle development by regulating the expression and alternative splicing of muscle-related genes.

 Abstract — The expectation-confirmation model (ECM) is one of the most widely used models for evaluating information system continuance, and this model has been extended to other study backgrounds, or expanded with other theoretical perspectives. However, combining ECM with other theories or investigating the background problem may produce some disparities, thus generating inaccurate conclusions. Habit is considered to be an important factor that influences the user’s continuance behavior. This paper thus critically examines seven pairs of relationships from the original ECM and the habit variable. A meta-analysis was used to tackle the development of ECM research over the last 10 years from a range of journals and conference papers published in 2005–2014. Forty-six journal articles and 19 conference papers were selected for analysis. The results confirm our prediction that a high effect size for the seven pairs of relationships was obtained (ranging from r=0.386 to r=0.588). Furthermore, a meta-analytic structural equation modeling was performed to simultaneously test all relationships. The results show that habit had a significant positive effect on continuance intention at p <=0.05 and that the six other pairs of relationships were significant at p <0.10. Based on the findings, we refined our original research model and an alternative model was proposed for understanding and predicting information system continuance. Some theoretical implications are also discussed.

Brefeldin A (BFA) is an fungal antibiotic that induces ER stress in eukaryotic cells. Cancer stem cells (CSCs) have indefinite potential for self-renewal and the capability to drive tumorigenesis. The effects of BFA on CSCs have not been fully investigated. In this article we investigated the inhibitory effects of BFA on human lung cancer A549 and H1299 cells. Cytotoxicity toward suspension cultures has been used as a method for the preliminary screening of drugs targeting CSCs. We showed that BFA effectively reduced the survival of suspension A549 cells (EC50 =similar to 30 ng/ml) by inducing apoptosis, and inhibited the clonogenic activity of A549 and H1299 CSCs at the same concentration range. We also demonstrated that BFA reduced the migration ability of A549 and H1299 cells. These results suggest that BFA can effectively suppress the progression of lung cancer during tumorigenesis and metastasis. The results of this study may help develop novel therapy for future treatment of lung cancer.

Cancer stem cells (CSCs) are a small subset of cancer cells with indefinite potential for self-renewal and the capacity to drive tumorigenesis. Brefeldin A (BFA) is an antibiotic that is known to block protein transport and induce endoplasmic reticulum (ER) stress in eukaryotic cells, but its effects on colorectal CSCs are unknown. We investigated the inhibitory effect of BFA on human colorectal cancer Colo 205 cells. We found that BFA effectively reduced the survival of suspension Colo 205 cells (IC50 = ~15 ng/mL) by inducing apoptosis, and inhibited the clonogenic activity of Colo 205 CSCs in tumorsphere formation assay and soft agar colony formation assay in the same nanogram per milliliter range. We also discovered that at such low concentrations, BFA effectively induced endoplasmic reticulum (ER) stress response as indicated by the increased mRNA expression of ER stress-related genes, such as glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), and C/EBP homologous protein (CHOP). Finally, we found that BFA reduced the activity of matrix metallopeptidase 9 (MMP-9). These findings suggest that BFA can effectively suppress the progression of colorectal cancer during the tumorigenesis and metastasis stages. These results may lead to the development of novel therapies for the treatment of colorectal cancer.

Areca nut (Areca catechu) is chewed as a medical and psychoactive food by roughly 10% of the world population. Areca nut chewing may lead to low birth weight, premature delivery and impaired muscle development. Our previous study showed that arecoline, a major alkaloid in the areca nut, inhibited the myogenic differentiation of C2C12 myoblastic cells. The clustering of acetylcholine receptors (AChRs) in the postsynaptic membrane at the neuromuscular junction (NMJ) by agrin, a signaling protein released by motor neurons, is critical for the development of functional muscles. Here, we further investigate whether arecoline affects the AChR clustering using cultured C2C12 myotubes. Rhodamine-conjugated α-bungarotoxin was used to detect the presence of AChR clusters. Our results showed that arecoline inhibited the formation of agrin-induced AChR clusters and destabilized agrin-induced or spontaneous AChR cluster formation. In addition, arecoline inhibited the expression of myogenin in C2C12 myotubes. These results shed light on the important role of arecoline on the detrimental effect of areca nut to muscle development.

In the mammalian central nervous system transcripts of certain synaptic components are localized near the synapse, allowing for rapid regulation of protein levels. Here we test whether an mRNA localization mechanism also exists in the postsynaptic specialization induced by agrin in C2C12 myotubes. RT-PCR showed that Chrna1 was co-purified with nicotinic acetylcholine receptor (AChR) isolated by affinity column or by ultracentrifugation. In addition, Stau1 was found to interact with Chrna1 mRNA, and knocking down of Stau1 by RNAi resulted in defective AChR clustering. These results suggest that mRNA localization also participates in the formation of mammalian neuromuscular junction (NMJ).

Areca nut (Areca catechu) is chewed regularly as a medical and psychoactive food by about 10% of the world population, in countries including India, Taiwan and parts of Southern Asia. Areca nut chewing during pregnancy has been associated with both lower birth weight and premature birth. Animals of low birth weights showed retardation of muscle development. Our previous study showed that arecoline, the major areca alkaloid, decreased the number of implanted embryos. Here we sought to determine the effects of arecoline in myogenic differentiation by in vitro assays using C2C12 myoblast cells. The results showed that arecoline higher than 0.4mM significantly increased apoptosis and decreased viability of C2C12 cells. Morphometric measurements of myotube formation and analyses of myogenic markers, myosin heavy chain and myogenin, revealed that myogenic differentiation was inhibited by 0.04–0.08mM arecoline. Moreover, phosphorylated but not total STAT3 was significantly inhibited by arecoline during myotube formation. These results indicate that arecoline inhibits the myogenic differentiation of C2C12 cells by reducing the activation of STAT3, an upstream regulator of myogenesis. Improved understanding of the effects of arecoline during myogenic differentiation may help to establish public health policies and to develop potential treatments for such patients.

The mutations of survival motor neuron (SMN) gene result in spinal muscular atrophy (SMA), a common neurodegenerative disease. Some of the motor neurons undergoing cell death is the predominant characteristic in SMA pathology. However, the viability and sensitivity to stresses of other cell types also need to be determined. In this article, we established HeLa stable cell line with inducible SMN knockdown to study its viability and sensitivity to oxidative stress. SMN knockdown in the HeLa stable cell line was induced by doxycycline. The proliferative and survival rates of SMN knockdown cells with or without hydrogen peroxide (H2O2) treatment were determined. Our results showed that the proliferative rate of SMN knockdown cells decreased only slightly compared with that of the cells without doxycycline treatment. In contrast, after H2O2 reached certain concentrations, the survival rate of SMN knockdown cells decreased significantly. Our data indicate that SMN knockdown alone is not critical to cell viability. However, when SMN knockdown cells are under stress, such as oxidative stress, their survival rate may significantly decrease. Our results will be helpful to prevent the detrimental effect caused by the cell death of non-motor neurons under stress in SMA patients. In addition, the cell model we established can be used to study the mechanism and screen drugs to prevent the detrimental effects in cases of SMA disease.

Areca nut (Areca catechu) is chewed by roughly 10% of the world population, including India, Taiwan and parts of China. Lower mean birth-weight and higher neonatal jaundice were reported in the babies of betel chewing pregnant women in 1982. Although areca nut chewing during pregnancy has been associated with lower birth weight and premature delivery, the mechanism of such complications is not entirely understood. A possible contributor, arecoline, a major alkaloid in the areca nut, has been reported to be cytotoxic and genotoxic. To determine the influence of arecoline on reproduction, we study the effects of arecoline on embryos during peri-implantation stages in mice. Mice consuming varying dosages of arecoline were checked for their ability to successfully produce viable embryos. In addition, trophoblast outgrowth from mice blastocysts was evaluated the survival status of the embryos. Our investigation revealed that arecoline decreased the number of implanted embryos in early pregnant mice. In addition, trophoblast outgrowth expansion of blastocysts was also inhibited by arecoline. These observations suggest that arecoline is toxic to mouse embryos as early as peri-implantation. Improved understanding of the effects of arecoline during embryogenesis may help to establish public health policies and to develop potential treatments for such patients.

Epstein-Barr virus (EBV) expresses two transcription factors, Rta and Zta, during the immediate-early stage of the lytic cycle to activate the transcription of viral lytic genes. Our immunoblotting and flow cytometry analyses find that moronic acid, found in galls of Rhus chinensis and Brazilian propolis, at 10microM inhibits the expression of Rta, Zta, and an EBV early protein, EA-D, after lytic induction with sodium butyrate. This study also finds that moronic acids inhibits the capacity of Rta to activate a promoter that contains an Rta-response element, indicating that moronic acid interferes with the function of Rta. On the other hand, moronic acid does not appear to influence with the transactivation function of Zta. Therefore, the lack of expression of Zta and EA-D after moronic acid treatment is attributable to the inhibition of the transactivation functions of Rta. Because the expression of Zta, EA-D and many EBV lytic genes depends on Rta, the treatment of P3HR1 cells with moronic acid substantially reduces the numbers of EBV particles produced by the cells after lytic induction. This study suggests that moronic acid is a new structural lead for anti-EBV drug development.