Prostate cancer has high metastatic potential. Men with higher urinary levels of the sleep hormone melatonin are much less likely to develop advanced prostate cancer compared with men with lower ...levels of melatonin. Melatonin has shown anticancer activity in experimental investigations. Nevertheless, the therapeutic effect of melatonin in metastatic prostate cancer has largely remained a mystery. Analyses of Gene Expression Omnibus data and human tissue samples indicated that levels of matrix metallopeptidase 13 (MMP‐13) expression are higher in prostate cancer patients than in healthy cancer‐free individuals. Mechanistic investigations revealed that melatonin inhibits MMP‐13 expression and the migratory and invasive capacities of prostate cancer cells via the MT1 receptor and the phospholipase C, p38, and c‐Jun signaling cascades. Importantly, tumor growth rate and metastasis to distant organs were suppressed by melatonin in an orthotopic prostate cancer model. This is the first demonstration showing that melatonin impedes metastasis of prostate cancer by suppressing MMP‐13 expression in both in vitro and in vivo models. Thus, melatonin is promising in the management of prostate cancer metastasis and deserves to undergo clinical investigations.
Melatonin acts on the MT1 receptor and inhibits phospholipase C (PLC) and p38 signal cascades, subsequently suppresses matrix metallopeptidase 13 (MMP‐13) expression through the c‐Jun‐dependent pathway, leading to the reduction of prostate cancer metastasis. This is the first indication that melatonin impedes metastasis via the targeting of MMP‐13 in prostate cancer cells, based on evidence from basic and clinical studies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Osteoblasts and osteoclasts are major cellular components in the bone microenvironment and they play a key role in the bone turnover cycle. Many risk factors interfere with this cycle and contribute ...to bone-wasting diseases that progressively destroy bone and markedly reduce quality of life. Melatonin (N-acetyl-5-methoxy-tryptamine) has demonstrated intriguing therapeutic potential in the bone microenvironment, with reported effects that include the regulation of bone metabolism, acceleration of osteoblastogenesis, inhibition of osteoclastogenesis and the induction of apoptosis in mature osteoclasts, as well as the suppression of osteolytic bone metastasis. This review aims to shed light on molecular and clinical evidence that points to possibilities of melatonin for the treatment of both osteoporosis and osteolytic bone metastasis. It appears that the therapeutic qualities of melatonin supplementation may enable existing antiresorptive osteoporotic drugs to treat osteolytic metastasis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Japanese self-addressed questions (SAQs) are either marked with SAQ question particles (i.e. kana, yara) or marked with modals daroo or desyoo. The present paper argues that the pragmatic profile of ...Japanese SAQs should not be limited to solitary contexts. The paper presents an experiment examining whether daroo-ka/desyoo-ka can be perceived as SAQs in the accompanied contexts. The results of the experiment indicate that Japanese SAQs can be felicitously uttered in the presence of a second (socially higher) person. Apart from the experimental study, this paper also presents a pilot study of comparing daroo-ka questions and plain information-seeking questions (i.e. those without daroo-ka) in urgent situation contexts. The preliminary results shed light on the fact that Japanese native speakers interpret daroo-ka questions as canonical questions in the performance of indirect speech acts.
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BFBNIB, NMLJ, NUK, PNG, UL, UM, UPUK
A high basal level of autophagic flux in bladder cancer (BC) cells prevents cell death and weakens chemotherapy efficacy. However, how autophagy influences cancer‐associated immunosuppression in BC ...remains undetermined. In this study, we observed a negative correlation between the autophagy‐related markers LC3‐II and programmed death ligand‐1 (PD‐L1) in BC cells. The autophagy inhibitors chloroquine (CQ) and bafilomycin A1 (Baf‐A1) increased PD‐L1 expression in BC cells through the ERK–JNK–c‐Jun signal‐transduction pathway. Moreover, the treatment of BC cells with CQ and Baf‐A1 inhibited hsa‐microRNA‐34a (miR‐34a) expression and miR‐34a overexpression in BC cells prevented the autophagy blockade–induced PD‐L1 expression; a negative correlation between miR‐34a and PD‐L1 expression was observed during treatment with autophagy inhibitors. Furthermore, miR‐34a overexpression induced the cytotoxic activity of natural killer cells against BC cells. Our results provide evidence that autophagy blockade and its regulatory pathway affect cancer‐associated immunosuppression through PD‐L1 elevation. Thus, the coadministration of autophagy inhibitors and a PD‐L1 immune checkpoint blockade provides a potential therapeutic approach for treating BC.
Graphical
Our model illustrates the pharmacological inhibition of autophagy could induce PD‐L1 expression in BC cells through the ERK–JNK–c‐Jun signaling transduction pathway and miR‐34a downregulation, revealing the effect of genetic and epigenetic regulation of autophagy on PD‐L1. In consequence, BC cells expressing PD‐L1 suppress NK cell cytotoxic activity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cancer-related bone erosion occurs frequently in bone metastasis and is associated with severe complications such as chronic bone pain, fractures, and lower survival rates. In recognition of the fact ...that the darkness hormone melatonin is capable of regulating bone homeostasis, we explored its therapeutic potential in bone metastasis. We found that melatonin directly reduces osteoclast differentiation, bone resorption activity and promotes apoptosis of mature osteoclasts. We also observed that melatonin inhibits RANKL production in lung and prostate cancer cells by downregulating the p38 MAPK pathway, which in turn prevents cancer-associated osteoclast differentiation. In lung and prostate bone metastasis models, twice-weekly melatonin treatment markedly reduced tumor volumes and numbers of osteolytic lesions. Melatonin also substantially lowered the numbers of TRAP-positive osteoclasts in tibia bone marrow and RANKL expression in tumor tissue. These findings show promise for melatonin in the treatment of bone metastases.
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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
The inflammatory chemokine (C-C motif) ligand 4 (CCL4) plays an important role in the pathogenesis and progression of cancer. In particular, higher serum CCL4 levels in patients with oral squamous ...cell carcinoma (OSCC) are associated with a more advanced stage of disease. OSCC accounts for approximately 95% of oral cancer in Taiwan and has a poor prognosis, due to aggressive local invasion and metastasis, leading to recurrence. OSCC spreads preferentially through lymphatic vessels and has the propensity to metastasize to the cervical lymph nodes even in the early stage of disease. Vascular endothelial growth factor C (VEGF-C) is an essential regulator of lymphangiogenesis. In particular, VEGF-C is specific to lymphatic vessel development, and VEGF-C expression levels have been found to directly correlate with lymph node metastasis in OSCC. However, it is unclear as to whether CCL4 correlates with VEGF-C expression and lymphangiogenesis in OSCC. We found that CCL4 increased VEGF-C expression and promoted lymphangiogenesis in oral cancer cells
and
. miR-195-3p mimic reversed CCL4-enhanced VEGF-C expression. CCL4 stimulation of oral cancer cells augmented JAK2 and STAT3 phosphorylation. Thus, CCL4 may be a new molecular therapeutic target for inhibition of lymphangiogenesis and metastasis in OSCC.
Chondrosarcoma is the second most frequently occurring type of bone malignancy that is characterized by the distant metastasis propensity. Vascular endothelial growth factor-C (VEGF-C) is the chief ...lymphangiogenic mediator, and makes crucial contributions to tumor lymphangiogenesis. Leptin is an adipocytokine and has been indicated to facilitate tumorigenesis, angiogenesis and metastasis. However, the effect of leptin on VEGF-C regulation and lymphangiogenesis in human chondrosarcoma has hugely remained a mystery. Our results showed a clinical correlation between leptin and VEGF-C as well as tumor stage in human chondrosarcoma tissues. We further demonstrated that leptin promoted VEGF-C production and secretion in human chondrosarcoma cells. The conditioned medium from leptin-treated chondrosarcoma cells induced lymphangiogenesis of human lymphatic endothelial cells. We also found that leptin-induced VEGF-C is mediated by the FAK, PI3K and Akt signaling pathway. Furthermore, the expression of microRNA-27b was negatively regulated by leptin via the FAK, PI3K and Akt cascade. Our study is the first to describe the mechanism of leptin-promoted lymphangiogenesis by upregulating VEGF-C expression in chondrosarcomas. Thus, leptin could serve as a therapeutic target in chondrosarcoma metastasis and lymphangiogenesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In recent years, osteosarcoma survival rates have failed to improve significantly with conventional treatment modalities because of the development of chemotherapeutic resistance. The human breast ...cancer resistance protein/ATP binding cassette subfamily G member 2 (BCRP/ABCG2), a member of the ATP‐binding cassette family, uses ATP hydrolysis to expel xenobiotics and chemotherapeutics from cells. CCN family member 2 (CCN2) is a secreted protein that modulates the biological function of cancer cells, enhanced ABCG2 protein expression and activation in this study via the α6β1 integrin receptor and increased osteosarcoma cell viability. CCN2 treatment downregulated miR‐519d expression, which promoted ABCG2 expression. In a mouse xenograft model, knockdown of CCN2 expression increased the therapeutic effect of doxorubicin, which was reversed by ABCG2 overexpression. Our data show that CCN2 increases ABCG2 expression and promotes drug resistance through the α6β1 integrin receptor, whereas CCN2 downregulates miR‐519d. CCN2 inhibition may represent a new therapeutic concept in osteosarcoma.
Chemoresistance is an important problem in osteosarcoma. CCN2 promotes drug resistance in osteosarcoma. CCN2 increases ABCG2 protein expression and activation in osteosarcoma
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Around half of all patients with oral squamous cell carcinoma (OSCC) present with lymphatic metastasis, a strong predictor of poor survival. Improving survival rates depends on preventing the first ...step in the "invasion
metastasis cascade," epithelial
to
mesenchymal transition (EMT), and developing antilymphangiogenesis therapies that antagonize lymphatic metastasis. The extracellular matrix
related protein WISP
1 (WNT1
inducible signaling pathway protein
1) stimulates bone remodeling and tumor progression. We have previously reported that WISP
1 promotes OSCC cell migration and lymphangiogenesis induced by vascular endothelial growth factor C (VEGF
C). This investigation sought to determine the role of WISP
1 in regulating EMT in OSCC. Our analysis of oral cancer data from The Cancer Genome Atlas (TCGA) database revealed significant and positive associations between levels of WISP
1 expression and clinical disease stage, as well as regional lymph node metastasis. We also found higher levels of WISP
1 expression in serum samples obtained from patients with OSCC compared with samples from healthy controls. In a series of in vitro investigations, WISP
1 activated EMT signaling via the FAK/ILK/Akt and Snail signaling transduction pathways and downregulated miR
153
3p expression in OSCC cells. Our findings detail how WISP
1 promotes EMT via the miR
153
3p/Snail axis in OSCC cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Bladder cancer (BC) is the second most common urological tumour in Western countries. Approximately, 80% of patients with BC will present with non-muscle invasive bladder cancer (NMIBC), whereas a ...quarter will have muscle invasive disease (MIBC) at the time of BC diagnosis. However, patients with NMIBC are at risk of BC recurrence or progression into MIBC, and an MIBC prognosis is determined by the presence of progression and metastasis. Matrix metalloproteinase 2 (MMP2), a type of matrix metalloproteinase (MMP), plays a major role in tumour invasion and is well-characterized in BC prognosis. In BC, the mechanisms regulating MMP2 expression, and, in turn, promote cancer invasion, have hardly been explored. Thrombospondin-4 (THBS4/TSP4) is a matricellular glycoprotein that regulates multiple biological functions, including proliferation, angiogenesis, cell adhesion and extracellular matrix modelling. Based on the results of a meta-analysis in the Gene Expression Profiling Interactive Analysis 2 database, we observed that TSP4 expression levels were consistent with overall survival (OS) rate and BC progression, with the highest expression levels observed in the advanced stages of BC and associated with poor OS rate. In our pilot experiments, incubation with recombinant TSP4 promoted the migration and invasion in BC cells. Furthermore, MMP2 expression levels increased after recombinant TSP4 incubation. TSP4-induced-MMP2 expression and cell motility were regulated via the AKT signalling pathway. Our findings facilitate further investigation into TSP4 silencing-based therapeutic strategies for BC.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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