KNOX and BELL transcription factors regulate distinct steps of diploid development in plants. In the green alga
KNOX and BELL proteins are inherited by gametes of the opposite mating types and ...heterodimerize in zygotes to activate diploid development. By contrast, in land plants such as
and
, KNOX and BELL proteins function in meristem maintenance and organogenesis during the later stages of diploid development. However, whether the contrasting functions of KNOX and BELL were acquired independently in algae and land plants is currently unknown. Here, we show that in the basal land plant species
, gamete-expressed
and
are required to initiate zygotic development by promoting nuclear fusion in a manner strikingly similar to that in
. Our results indicate that zygote activation is the ancestral role of KNOX/BELL transcription factors, which shifted toward meristem maintenance as land plants evolved.
Anti-EGFR mAb is reported to induce EGFR internalization in colorectal cancer cells. However, the biological relevance of EGFR internalization with anti-EGFR mAb is unknown. Therefore, the relevance ...of EGFR downregulation with anti-EGFR mAb to antitumor activity in colorectal cancer cells was investigated. Quantification of EGFR on the cell surface before cetuximab treatment was assessed by flow cytometry, and its growth-inhibitory effects were measured by Trypan blue exclusion, in 10
wild-type colorectal cancer cell lines, but there was no significant correlation between EGFR number and its growth-inhibitory effect. However, a significant correlation existed between the percentage decrease in the number of EGFRs after cetuximab treatment and its growth-inhibitory effect in those cell lines. Treatment with TGFα, a ligand for EGFR, induced EGFR internalization in colorectal cancer cells, but most EGFRs subsequently recycled to the cell surface, consistent with previous studies. While cetuximab treatment induced EGFR internalization, most receptors subsequently translocated into the late endosome, leading to lysosomal degradation, as revealed by immunoblotting and double immunofluorescence. Cetuximab-sensitive colorectal cancer cells showed greater EGFR internalization, stronger cell growth inhibition, and more augmented apoptotic signals than nonsensitive cells. IHC for EGFR, performed using an EGFR pharmDx Kit (mouse anti-human EGFR mAb clone 2-18C9), in clinical specimens before and after anti-EGFR mAb therapy in 13 colorectal cancer patients showed a significant correlation between the response to anti-EGFR mAb and decreased staining after therapy.
This report clearly demonstrates that anti-EGFR mAb facilitates internalization and subsequent degradation of EGFRs in lysosomes, which is an important determinant of the efficacy of anti-EGFR mAb treatment for colorectal cancer.
.
Chaperone‐mediated autophagy (CMA) is a lysosomal degradation pathway of selective soluble proteins. Lysosome‐associated membrane protein type 2a (LAMP2A) is the key receptor protein of CMA; ...downregulation of LAMP2A leads to CMA blockade. Although CMA activation has been involved in cancer growth, CMA status and functions in non–small cell lung cancer (NSCLC) by focusing on the roles in regulating chemosensitivity remain to be clarified. In this study, we found that LAMP2A expression is elevated in NSCLC cell lines and patient's tumors, conferring poor survival and platinum resistance in NSCLC patients. LAMP2A knockdown in NSCLC cells suppressed cell proliferation and colony formation and increased the sensitivity to chemotherapeutic drugs in vitro. Furthermore, we found that intrinsic apoptosis signaling is the mechanism of cell death involved with CMA blockade. Remarkably, LAMP2A knockdown repressed tumorigenicity and sensitized the tumors to cisplatin treatment in NSCLC‐bearing mice. Our discoveries suggest that LAMP2A is involved in the regulation of cancer malignant phenotypes and represents a promising new target against chemoresistant NSCLC.
Lysosome‐associated membrane protein type 2a (LAMP2A) is the key receptor protein of chaperone‐mediated autophagy (CMA). Downregulation of LAMP2A leads to CMA blockade. Our discoveries suggest that LAMP2A is involved in the regulation of cancer malignant phenotypes through CMA modulation and represents a promising new target against chemoresistant non–small cell lung cancer (NSCLC).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Mitochondria play an essential role in intracellular energy metabolism. This study described the involvement of Bombyx mori nucleopolyhedrovirus (BmNPV) GP37 (BmGP37) in host mitochondria. Herein, ...the proteins associated with host mitochondria isolated from BmNPV-infected or mock-infected cells by two-dimensional gel electrophoresis were compared. One mitochondria-associated protein in virus-infected cells was identified as BmGP37 by liquid chromatography-mass spectrometry analysis. Furthermore, the BmGP37 antibodies were generated, which could react specifically with BmGP37 in the BmNPV-infected BmN cells. Western blot experiments showed that BmGP37 was expressed at 18 h post-infection and was verified as a mitochondria-associated protein. Immunofluorescence analysis demonstrated that BmGP37 localized to the host mitochondria during BmNPV infection. Furthermore, western blot analysis revealed that BmGP37 is a novel component protein of the occlusion-derived virus (ODV) of BmNPV. The present results indicated that BmGP37 is one of the ODV-associated proteins and may have important roles in host mitochondria during BmNPV infection.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Although right‐sided colorectal cancer (CRC) shows a worse prognosis than left‐sided CRC, the underlying mechanism remains unclear. We established patient‐derived organoids (PDOs) from left‐ and ...right‐sided CRCs and directly compared cell proliferation and invasion capability between them. We then analyzed the expression of numerous genes in signal transduction pathways to clarify the mechanism of the differential prognosis. Cell proliferation activity and invasion capability in right‐sided cancer PDOs were significantly higher than in left‐sided cancer PDOs and normal PDOs, as revealed by Cell Titer Glo and transwell assays, respectively. We then used quantitative RT‐PCR to compare 184 genes in 30 pathways among right‐sided and left‐sided cancer and normal PDOs and found that the TIMP1 mRNA level was highest in right‐sided PDOs. TIMP1 protein levels were upregulated in right‐sided PDOs compared with normal PDOs but was downregulated in left‐sided PDOs. TIMP1 knockdown with shRNA significantly decreased cell proliferation activity and invasion capability in right‐sided PDOs but not in left‐sided PDOs. Moreover, TIMP1 knockdown significantly decreased pFAK and pAkt expression levels in right‐sided PDOs but not in left‐sided PDOs. A database analysis of The Cancer Genome Atlas revealed that TIMP1 expression in right‐sided CRCs was significantly higher than in left‐sided CRCs. Kaplan–Meier survival analysis showed significantly shorter overall survival in high‐TIMP1 patients versus low‐TIMP1 patients with right‐sided CRCs but not left‐sided CRCs. Our data suggest that TIMP1 is overexpressed in right‐sided CRCs and promotes cell proliferation and invasion capability through the TIMP1/FAK/Akt pathway, leading to a poor prognosis. The TIMP1/FAK/Akt pathway can be a target for therapeutic agents in right‐sided CRCs.
Our study suggests that TIMP1 is overexpressed in the right‐sided colorectal cancer, and promotes cell proliferation and invasion capability through TIMP1/FAK/Akt pathway, leading to poor prognosis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal fibrosis, resulting in poor patient prognosis. An aberrant recapitulation of developmental lung ...gene expression, including genes for transforming growth factor (TGF)‐β and WNT, has been widely implicated in the pathogenic IPF wound healing process that results from repetitive alveolar epithelial injury. Extracellular vesicles (EVs) have been shown to carry bioactive molecules and to be involved in various physiological and pathological processes. Here, we demonstrate that, by attenuating WNT signalling, human bronchial epithelial cell‐derived EVs (HBEC EVs) inhibit TGF‐β mediated induction of both myofibroblast differentiation and lung epithelial cellular senescence. This effect of HBEC EVs is more pronounced than that observed with mesenchymal stem cell‐derived EVs. Mechanistically, the HBEC EV microRNA (miRNA) cargo is primarily responsible for attenuating both myofibroblast differentiation and cellular senescence. This attenuation occurs via inhibition of canonical and non‐canonical WNT signalling pathways. Among enriched miRNA species present in HBEC EVs, miR‐16, miR‐26a, miR‐26b, miR‐141, miR‐148a, and miR‐200a are mechanistically involved in reducing WNT5A and WNT10B expression in LFs, and in reducing WNT3A, WNT5A, and WNT10B expression in HBECs. Mouse models utilizing intratracheal administration of EVs demonstrate efficient attenuation of bleomycin‐induced lung fibrosis development accompanied by reduced expression of both β‐catenin and markers of cellular senescence. These findings indicate that EVs derived from normal resident lung HBECs may possess anti‐fibrotic properties. They further suggest that, via miRNA‐mediated inhibition of TGF‐β‐WNT crosstalk, HBEC EVs administration can be a promising anti‐fibrotic modality of treatment for IPF.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A 66-year-old Japanese man receiving systemic chemotherapy for advanced gastric cancer presented with exertional dyspnea. D-dimer was elevated in the blood. Echocardiography revealed pulmonary ...hypertension, and a ventilation-perfusion scan indicated decreased perfusion in the bilateral lungs. Cardiac catheterization showed no evidence of pulmonary artery embolization and revealed cytologically confirmed adenocarcinoma. Thus, pulmonary tumor thrombotic microangiopathy (PTTM) was diagnosed. The patient died of respiratory failure on the 17th hospitalization day despite systemic chemotherapy. Retrospective serological testing revealed increased vascular endothelial growth factor in the pulmonary artery blood. This is a rare case with antemortem cytologically proven PTTM mediated by VEGF.
We herein report two cases of cerebrospinal fluid (CSF) rhinorrhea associated with lung infiltrates. One patient presented with symptomatic non-resolving pneumonia, while the other was asymptomatic. ...In both cases, the lung infiltrates completely resolved when CSF leakage had subsided. Pulmonary involvement in CSF rhinorrhea is under-recognized, and despite being the definitive treatment, surgery for CSF rhinorrhea is typically postponed due to the presence of lung infiltrates. However, meningitis is a serious complication due to a delay in surgical management. Physicians should be made aware that CSF rhinorrhea is a potential cause of intractable lung infiltrates.
To overcome the problem of overlooking colorectal tumors, a new and highly sensitive modality of colonoscopy is needed. Moreover, it is also important to establish a new modality to evaluate viable ...tumor volume in primary lesions of colorectal cancer (CRC) during chemotherapy. Therefore, we carried out molecular imaging of colorectal tumors targeting epidermal growth factor receptor (EGFR), which is highly expressed on tumor cells, for evaluating chemotherapeutic efficacy and for endoscopic detection of colorectal adenomas. We first attempted to image five CRC cell lines with various levels of EGFR expression using an Alexa Fluor‐labeled anti‐EGFR monoclonal antibody (AF‐EGFR‐Ab). A strong fluorescence signal was observed in the cells depending on the level of EGFR expression. When nude mice xenografted with LIM1215 CRC cells, which highly express EGFR, were i.v. injected with AF‐EGFR‐Ab, a strong fluorescence signal appeared in the tumor with a high signal to noise ratio, peaking at 48 hours after injection and then gradually decreasing, as shown using an IVIS Spectrum system. When the xenografted mice were treated with 5‐fluorouracil, fluorescence intensity in the tumor decreased in proportion to the viable tumor cell volume. Moreover, when the colorectum of azoxymethane‐treated rats was observed using a thin fluorescent endoscope with AF‐EGFR‐Ab, all 10 small colorectal adenomas (≤3 mm) were detected with a clear fluorescence signal. These preliminary results of animal experiments suggest that EGFR‐targeted fluorescent molecular imaging may be useful for quantitatively evaluating cell viability in CRC during chemotherapy, and also for detecting small adenomas using a fluorescent endoscope.
Molecular imaging targeting epidermal growth factor receptor (EGFR) showed utility for evaluating therapeutic efficacy, as indicated by viable cell volume, more accurately than tumor size. This EGFR imaging method was also useful in detecting colorectal adenoma in rat colorectum. This imaging method may lead to advancements in early detection and improved diagnosis of colorectal tumors, as well as therapeutic evaluation of colorectal cancer.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The Bombyx mori nucleopolyhedrovirus (BmNPV) La is a variant BmNPV strain isolated in Laos. La has different features from BmNPV type strain T3 in virulence, production of the polyhedrin protein, and ...the formation of multicapsid occlusion-derived viruses. Here, the whole-genome sequence of La was compared to the sequences of nine BmNPV and two Bombyx mandarina nucleopolyhedrovirus strains. The complete La genome consisted of 127,618 base pairs with a G + C content of 40.3% and contained putative 136 open reading frames encoding more than 60 amino acids. The La genome lacked the
bro-b
gene and had the highest identity with that of the T3 strain. A comparison of the transcriptomes of La- and T3-infected cells showed that the expression levels of the
polyhedrin
and
cathepsin
genes were greater in cells infected with La as compared to those infected with T3. Interestingly, the virus genes with different RNA levels between the two BmNPV strains were assembled into five clusters in the genome of La. Also, the RNA levels of host ribosomal protein genes were significantly decreased in cells infected with La as compared to those infected with T3.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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