Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of ...diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5‐fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X‐linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor β receptor 2‐mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling.
Metformin and phenformin decreased the expression of pro‐apoptotic proteins by inhibiting STAT3 phosphorylation at Ser‐727 and suppressed invasion and migration by inhibiting TGFBR2‐mediated signaling
Microplastic pollution causes a major concern in the marine environment due to their worldwide distribution, persistence, and adverse effects of these pollutants in the marine ecosystem. Despite its ...global presence, there is still a lack of information on the effect of microplastics on marine organisms at the molecular level. Herein we demonstrated ingestion and egestion of nano- (0.05 μm) and micro-sized (0.5 and 6 μm) polystyrene microbeads in the marine copepod Paracyclopina nana, and examined molecular responses to exposure to microbeads with in vivo endpoints such as growth rate and fecundity. Also, we proposed an adverse outcome pathway for microplastic exposure that covers molecular and individual levels. This study provides the first insight into the mode of action in terms of microplastic-induced oxidative stress and related signaling pathways in P. nana.
Conventional screening methods for deubiquitinating enzymes (DUBs) have important limitations. A loss-of-function study based on the knockout of DUB genes in mammalian cells can provide an excellent ...model for exploring DUB function. Here, we used CRISPR-Cas9 to perform genome-scale knockout of the entire set of genes encoding ubiquitin-specific proteases (USPs), a DUB subfamily, and then systematically screened for DUBs that stabilize the Cdc25A oncoprotein. USP3 was identified as a deubiquitinase of Cdc25A. USP3 depletion reduces the Cdc25A protein level, resulting in a significant delay in cell-cycle progression, and reduces the growth of cervical tumor xenografts in nude mice. Clinically, USP3 expression is positively correlated with Cdc25A protein expression and the poorest survival in breast cancer. We envision that our DUB knockout library kit will facilitate genome-scale screening of functional DUBs for target proteins of interest in a wide range of biomedical fields.
Hyaluronic acid synthase 2 (HAS2) is suggested to play a critical role in malignancy and is abnormally expressed in many carcinomas. However, its role in colorectal cancer (CRC) malignancy and ...specific signaling mechanisms remain obscure. Here, we report that HAS2 was markedly increased in both CRC tissue and malignant CRC cell lines. Depletion of HAS2 in HCT116 and DLD1 cells, which express high levels of HAS2, critically increased sensitivity of radiation/oxaliplatin‐mediated apoptotic cell death. Moreover, downregulation of HAS2 suppressed migration, invasion and metastasis in nude mice. Conversely, ectopic overexpression of HAS2 in SW480 cells, which express low levels of HAS2, showed the opposite effect. Notably, HAS2 loss‐ and gain‐of‐function experiments revealed that it regulates CRC malignancy through TGF‐β expression and SMAD2/Snail downstream components. Collectively, our findings suggest that HAS2 contributes to malignant phenotypes of CRC, at least partly, through activation of the TGF‐β signaling pathway, and shed light on the novel mechanisms behind the constitutive activation of HAS2 signaling in CRC, thereby highlighting its potential as a therapeutic target.
HAS2 is preferentially overexpressed in malignant‐type CRC cancer cells compared with that in mildtype CRC. By studying cells with loss‐ and gain‐of‐function of HAS2, we demonstrated that HAS2 is a critical regulator for the malignant behavior of CRC such as therapeutic resistance or metastatic ability. Importantly, HAS2 promoted CRC malignancy through HA ligand‐independent TGF‐β regulation.
Surface-enhanced Raman scattering (SERS) is an ultrasensitive molecular screening technique with greatly enhanced Raman scattering signals from trace amounts of analytes near plasmonic ...nanostructures. However, research on the development of a sensor that balances signal enhancement, reproducibility, and uniformity has not yet been proposed for practical applications. In this study, we demonstrate the potential of the practical application for detecting or predicting asymptomatic breast cancer from human tears using a portable Raman spectrometer with an identification algorithm based on multivariate statistics. This potentiality was realized through the fabrication of a plasmonic SERS substrate equipped with a well-aligned, gold-decorated, hexagonal-close-packed polystyrene (Au/HCP-PS) nanosphere monolayer that provided femtomole-scale detection, giga-scale enhancement, and <5% relative standard deviation for reliability and reproducibility, regardless of the measuring site. Our results can provide a first step toward developing a noninvasive, real-time screening technology for detecting asymptomatic tumors and preventing tumor recurrence.
Colorectal cancer (CRC) has a 5-year survival rate of <10%, as it can metastasize to the lungs and liver. Anticancer drugs and targeted therapies used to treat metastatic colorectal cancer have ...insufficient therapeutic efficacy and are associated with complications. Therefore, research to develop new targeted therapeutics is necessary. Here, we present a novel discovery that intracellular adhesion molecule-1 (ICAM-1) is a potential therapeutic target to enhance therapeutic effectiveness for CRC. ICAM-1 is an important regulator of cell-cell interactions and recent studies have shown that it promotes malignancy in several carcinomas. However, little is known about its effect on CRC. Therefore, we conducted a study to define the mechanism by which ICAM-1 acts. ICAM-1 is phosphorylated by tyrosine-protein kinase Met (c-MET), and phosphorylated ICAM-1 can interact with SRC to increase SRC activity. Consequently, ICAM-1 may further accelerate SRC signaling, promoting the malignant potential of cancer. In addition, treatment with antibodies targeting ICAM-1 showed excellent therapeutic effects in reducing metastasis and angiogenesis. These findings suggest for the first time that ICAM-1 is an important adapter protein capable of mediating the c-MET-SRC signaling axis. Therefore, ICAM-1 can be used as a novel therapeutic target and a metastatic marker for CRC.
Radiotherapy is increasingly used in the treatment of joint diseases, but limited information is available on the effects of radiation on cartilage. Here, we characterize the molecular mechanisms ...leading to cellular senescence in irradiated primary cultured articular chondrocytes. Ionizing radiation (IR) causes activation of ERK, in turn generating intracellular reactive oxygen species (ROS) with induction of senescence-associated β-galactosidase (SA-β-gal) activity. ROS activate p38 kinase, which further promotes ROS generation, forming a positive feedback loop to sustain ROS-p38 kinase signaling. The ROS inhibitors, nordihydroguaiaretic acid and GSH, suppress phosphorylation of p38 and cell numbers positive for SA-β-gal following irradiation. Moreover, inhibition of the ERK and p38 kinase pathways leads to blockage of IR-induced SA-β-gal activity via reduction of ROS generation. Although JNK is activated by ROS, this pathway is not associated with cellular senescence of chondrocytes. Interestingly, IR triggers down-regulation of SIRT1 protein expression but not the transcript level, indicative of post-transcriptional cleavage of the protein. SIRT1 degradation is markedly blocked by SB203589 or MG132 after IR treatment, suggesting that cleavage occurs as a result of binding with p38 kinase, followed by processing via the 26 S proteasomal degradation pathway. Overexpression or activation of SIRT1 significantly reduces the IR-induced senescence phenotype, whereas inhibition of SIRT1 activity induces senescence. Based on these findings, we propose that IR induces cellular senescence of articular chondrocytes by negative post-translational regulation of SIRT1 via ROS-dependent p38 kinase activation.
We report triboelectric nanogenerators （TENGs） composed of a flexible and cost-effective gold-coated conductive textile （CT） to convert wind energy into electricity. The Au-coated CT is employed ...because of its high surface roughness resulting from Au nanodots distributed on microsized fibers. Thus, the Au-coated CT with nano/microarchitecture plays an important role in enhancing the effective contact area as well as the output performance of the TENG. Moreover, the surface roughness of the Au-coated CT is controlled by adjusting the Au thermal deposition time or tailoring the diameter of the Au nanodots. At an applied wind speed of 10 m.s-1, a wind-based TENG （W-TENG） with dimensions of 75 mm × 12 mm ×25 mm produces an open-circuit voltage （Voc） of - 39 V and a short-circuit current （Isc） of - 3 A by using the airflow-induced vibrations of an optimized Au-coated CT between two flat polydimethylsiloxane （PDMS） layers. To further specify the device performance, the electric output of the W-TENG is analyzed by varying several parameters such as the distance between the PDMS layer and Au-coated CT, applied wind speed, external load resistance, and surface roughness of the PDMS layers. Introducing an inverse micropyramid architecture on the PDMS layers further improves the output performance of the W-TENG, which exhibits the highest Voc （- 49 V） and Isc （- 5μA） values at an applied wind speed of 6.8 m.s-1. Additionally, the reliability of the W-TENG is also tested by measuring its output current during long-term cyclic operation. Furthermore, the rectified output signals observed by the W-TENG device are used as a direct power source to light 45 green commercial light-emitting diodes connected in series and also to charge capacitors （100 and 4.7μF）. Finally, the output performance of the W-TENG device in an actual windy situation is also investigated.
Abstract
Lineage tracing in mice indicates that
LGR5
is an adult stem cell marker in multiple organs, such as the intestine, stomach, hair follicles, ovary, and mammary glands. Despite many studies ...exploring the presence of
LGR5
cells in human tissues, little is known about its expression profile in either human mammary tissue or pathological lesions. In this study we aim to investigate
LGR5
expression in normal, benign, and malignant lesions of the human breast using RNA in situ hybridization.
LGR5
expression has not been observed in normal lactiferous ducts and terminal duct lobular units, whereas
LGR5
-positive cells have been specifically observed in the basal myoepithelium of ducts in the regenerative tissues, ductal carcinoma in situ, and in ducts surrounded by invasive cancer cells. These findings suggest
LGR5
marks facultative stem cells that are involved in post injury regeneration instead of homeostatic stem cells.
LGR5
positivity was found in 3% (9 of 278 cases) of invasive breast cancers (BC), and it showed positive associations with higher histologic grades (
P
= 0.001) and T stages (
P
< 0.001), while having negative correlations with estrogen receptor (
P
< 0.001) and progesterone receptor (
P
< 0.001) expression. Remarkably, all
LGR5
-positive BC, except one, belong to triple-negative BC (TNBC), representing 24% (9 of 38 cases) of all of them.
LGR5
histoscores have no correlations with EGFR, CK5/6, Ki-67, or P53 expression. Additionally, no β-catenin nuclear localization was observed in
LGR5
-positive BC, indicating that canonical Wnt pathway activation is less likely involved in
LGR5
expression in BC. Our results demonstrate that
LGR5
expression is induced in regenerative conditions in the myoepithelium of human mammary ducts and that its expression is only observed in TNBC subtype among all invasive BC. Further studies regarding the functional and prognostic impact of
LGR5
in TNBC are warranted.
We report the development of a surface-enhanced Raman spectroscopy sensor chip by decorating gold nanoparticles (AuNPs) on ZnO nanorod (ZnO NR) arrays vertically grown on cellulose paper (C). We show ...that these chips can enhance the Raman signal by 1.25 × 107 with an excellent reproducibility of <6%. We show that we can measure trace amounts of human amniotic fluids of patients with subclinical intra-amniotic infection (IAI) and preterm delivery (PTD) using the chip in combination with a multivariate statistics-derived machine-learning-trained bioclassification method. We can detect the presence of prenatal diseases and identify the types of diseases from amniotic fluids with >92% clinical sensitivity and specificity. Our technology has the potential to be used for the early detection of prenatal diseases and can be adapted for point-of-care applications.
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