Hormones, especially steroids, are closely involved in the physiological functions and proliferation of various target tissues and have long been known to play a key role in the tumorigenesis or ...carcinogenesis of these target tissues ....
In situations of a disaster, it has been observed that the damage suffered by women and men is not equal. The vulnerability of women during disasters has been the focus of several studies and ...disaster management guidelines. Records show that there were more women victims than men victims in both the Great Hanshin-Awaji Earthquake in 1995 and the Great East Japan Earthquake (GEJE) in 2011. Biologically speaking, women are physically less fit than men are; hence, they are more susceptible to physical disabilities induced by disasters and may be disadvantaged in evacuation situations. However, vulnerability of women during disasters is a complex problem that involves physical fitness, as well as other various factors. In the Sendai Framework for Disaster Risk Reduction 2015-2030 (SFDRR) adopted in 2015, prioritized actions such as “Build Back Better” were defined based on the GEJE experiences. In the SFDRR, in addition to vulnerability of women during disasters, medical services including maternal, newborn, and child health and sexual and reproductive health are considered the key factors for disaster risk reduction. This has been discussed in all phases of disaster risk reduction planning and post-disaster response. These findings suggest that the role of obstetrics and gynecology is comprehensive and important as a part of disaster medicine at the local and national levels, as recommended in the SFDRR. In this review, we summarized the management of women’s health and gynecological responses during disasters and considered the importance of women as stakeholders in disaster risk reduction.
p62/SQSTM1 (p62) is a multifunctional protein implicated in several signal transduction pathways and selectively degraded by autophagy, a process for lysosomal degradation of both protein and ...organelle. p62 was also recently reported to be overexpressed in various malignancies and its inhibition to suppress carcinoma cell proliferation. However, its correlation with autophagy in carcinoma cells has remained largely unknown. Therefore, in this study, we examined the effects of p62 inhibition on the regulation of autophagy and cell survival in p62‐positive carcinoma cells. p62‐silencing dramatically suppressed cell proliferation and induced autophagy in p62 expressing PC9 and A549 cells. Electron microscopical analysis revealed the formation of autophagosomes with multilayer membranes caused by p62‐silencing. p62 silencing‐mediated reduced cell viability was restored by both genomic and pharmacological inhibition of autophagy but not that of apoptosis. These findings were also detected in several types of carcinoma cell lines including adenocarcinomas and squamous cell carcinomas. Results of our present study revealed that an inhibition of p62 resulted in the formation of mis‐regulated autophagosomes with multilayer membranes and an autophagic cell death, and p62 can therefore be an attractive target for the development of anti‐neoplastic agents.
p62/SQSTM1 (p62) is a multifunctional protein implicated in several signal transduction pathways and selectively degraded by autophagy, a process for lysosomal degradation of protein and organelle. Results of our present study revealed that p62‐silencing resulted in the formation of mis‐regulated multilayer autophagosomes and an autophagic cell death, and p62 can therefore be an attractive target for the development of anti‐neoplastic agents.
Abstract Several growth factors and their receptors, such as epidermal growth factor receptor, have been studied as prognostic biomarkers for many epithelial malignancies. The signal transduction ...cascade of those receptors includes RAS/RAF/ERK, PI3K/Akt/mTOR, and STAT3 pathways. The aim of this study was to investigate the expression levels of several key proteins of those pathways in patients with oral squamous cell carcinoma (OSCC) and oral epithelial precursor lesions (OEPLs), and to correlate the expressions of these proteins with clinicopathologic features and prognosis. Fifteen leukoplakia (LP), 15 low-grade epithelial dysplasia, 15 high-grade epithelial dysplasia (HD), and 132 OSCC specimens were immunohistochemically examined for KRAS, HRAS, NRAS, BRAF, pERK1/2, pAkt, pmTOR, and pSTAT3 expression. Immunoreactivity for these molecules predominantly occurred in regions OEPL basal to prickle layers and in most OSCC cells. KRAS and NRAS expression was significantly lower in OSCC than in OEPLs, while pAkt and pmTOR showed higher expression in OSCC than in OEPLs. pERK1/2 expression was significantly higher in HD than in LP. In OSCC, KRAS and NRAS immunoreactivity was significantly higher in advanced age and male gender. In addition, higher immunoreactivity was shown in pERK1/2 in female gender and advanced TNM stage, pAkt in advanced T classification and cases without postoperative metastasis, pmTOR in advanced mode of invasion, and pSTAT3 in invasion depth. Correlations between these markers and clinicopathological variables were also noted. MAPK, Akt, and STAT3 pathways might play diverse roles in oral carcinogenesis.
Metastatic breast cancer is a highly lethal disease, and it is very important to evaluate the biomarkers associated with distant metastasis. However, molecular features of distant metastasis remain ...largely unknown in breast cancer. Estrogens play an important role in the progression of breast cancer and the majority of stage IV breast carcinomas express estrogen receptor (ER). Therefore, in this study, we examined molecular markers associated with distant metastasis in ER‐positive breast carcinoma by microarray and immunohistochemistry. When we examined the gene expression profile of ER‐positive stage IV breast carcinoma tissues (n = 7) comparing ER‐positive stage I‐III cases (n = 11) by microarray analysis, we newly identified OLFM4, LY6D and S100A7, which were closely associated with the distant metastasis. Subsequently, we performed immunohistochemistry for OLFM4, LY6D and S100A7 in 168 ER‐positive breast carcinomas. OLFM4, LY6D and S100A7 immunoreactivities were significantly associated with stage, pathological T factor, distant metastasis and Ki67 status in the ER‐positive breast carcinomas. Moreover, these immunoreactivities were significantly associated with a worse prognostic factor for distant metastasis‐free and breast cancer‐specific survival in ER‐positive stage I‐III breast cancer patients. However, when we performed immunohistochemistry for OLFM4, LY6D and S100A7 in 40 ER‐negative breast carcinomas, these immunoreactivities were not generally associated with the clinicopathological factors examined, including distant metastasis and prognosis of patients, in this study. These results suggest that OLFM4, LY6D and S100A7 immunoreactivity are associated with an aggressive phenotype of ER‐positive breast carcinoma, and these are potent markers for distant metastasis of ER‐positive breast cancer patients.
This is the first report that demonstrates the gene expression profile of estrogen receptor (ER)‐positive stage IV breast carcinoma, and we newly identified that OLFM4, LY6D and S100A7 were associated with the distant metastasis. A subsequent immunohistochemical analysis revealed that OLFM4, LY6D and S100A7 immunoreactivity were significantly associated with an aggressive phenotype of ER‐positive breast carcinoma including distant metastasis and a worse prognostic factor of the patients. Our present results suggest that OLFM4, LY6D and S100A7 are potent markers for distant metastasis, and could become important therapeutic targets in ER‐positive breast cancer patients.
The importance of sex hormones, especially estrogen, in the pathogenesis of non-small-cell lung cancer (NSCLC) has attracted attention due to its high incidence among young adults and nonsmokers, ...especially those who are female. Cancer-associated fibroblasts (CAFs) reside in the cancer stroma and influence cancer growth, invasion, metastasis, and acquisition of drug resistance through interactions with cancer cells and other microenvironmental components. Hormone-mediated cell-cell interactions are classic cell-cell interactions and well-known phenomena in breast cancer and prostate cancer CAFs. In cancers of other organs, including NSCLC, the effects of CAFs on hormone-receptor expression and hormone production in cancer tissues have been reported; however, there are few such studies. Many more studies have been performed on breast and prostate cancers. Recent advances in technology, particularly single-cell analysis techniques, have led to significant advances in the classification and function of CAFs. However, the importance of sex hormones in cell-cell interactions of CAFs in NSCLC remains unclear. This review summarizes reports on CAFs in NSCLC and sex hormones in cancer and immune cells surrounding CAFs. Furthermore, we discuss the prospects of sex-hormone research involving CAFs in NSCLC.
Estrogen receptors promote target gene transcription when they form a dimer, in which two identical (homodimer) or different (heterodimer) proteins are bound to each other. In hormone-dependent ...cancers, hormone receptor dimerization plays pivotal roles, not only in the pathogenesis or development of the tumors, but also in the development of therapeutic resistance. Protein⁻protein interactions (PPIs), including dimerization and complex formation, have been also well-known to be required for proteins to exert their functions. The methods which could detect PPIs are genetic engineering (i.e., resonance energy transfer) and/or antibody technology (i.e., co-immunoprecipitation) using cultured cells. In addition, visualization of the target proteins in tissues can be performed using antigen⁻antibody reactions, as in immunohistochemistry. Furthermore, development of microscopic techniques (i.e., electron microscopy and confocal laser microscopy) has made it possible to visualize intracellular and/or intranuclear organelles. We have recently reported the visualization of estrogen receptor dimers in breast cancer tissues by using the in situ proximity ligation assay (PLA). PLA was developed along the lines of antibody technology development, and this assay has made it possible to visualize PPIs in archival tissue specimens. Localization of PPI in organelles has also become possible using super-resolution microscopes exceeding the resolution limit of conventional microscopes. Therefore, in this review, we summarize the methodologies used for studying PPIs in both cells and tissues, and review the recently reported studies on PPIs of hormones.
The therapeutic strategy is determined by protein expression using immunohistochemistry of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) in ...formalin-fixed paraffin-embedded (FFPE) breast cancer tissues. However, few proteins function independently, and many of them functions due to protein-protein interactions (PPIs) with other proteins. Therefore, it is important to focus on PPIs. This review summarizes the PPIs of ER and HER2 in breast cancer, especially those using a proximity ligation assay that can visualize PPIs in FFPE tissues. In particular, assessing the interaction of CEACAM6 with HER2 may serve as a surrogate marker for the efficacy of trastuzumab in patients with breast cancer. Therefore, in this review, the technique used to detect the interaction of CEACAM6 and HER2 in routinely processed pathological specimens will be applied to the clinical practice of drug selection. We showed the possibility as a novel pathological examination method using PPIs.
The great majority of breast carcinomas arising in postmenopausal women are estrogen dependent or positive for estrogen receptor (ER) in carcinoma cells despite markedly low plasma or circulating ...estrogen concentrations. In these patients, biologically active estrogens are locally produced from circulating inactive steroids including adrenal androgens in an intracrine mechanism in the breast cancer tissues and confer estrogenic activities on carcinoma cells. A series of enzymes are involved in this intra‐tumoral or in situ production of estrogens in breast carcinoma tissues but aromatase, a member of the cytochrome P450 family, is a key enzyme of estrogen production through conversion from circulating adrenal androgens in estrogen‐dependent postmenopausal breast cancer. It then becomes important to identify the sites of this estrogen production. There has been, however, controversy regarding intra‐tumoral localization of aromatase in breast carcinoma, especially whether intra‐tumoral production of estrogens through aromatase occurs in carcinoma or stromal cells. The enzyme was demonstrated to be expressed in both carcinoma and stromal cells in breast carcinoma tissues on immunohistochemistry with a well‐characterized mAb 677 and combined laser capture microdissection/qualitative reverse transcriptase–polymerase chain reaction. Intra‐tumoral aromatase in both of these cell types was subsequently demonstrated to be induced by carcinoma–stromal interactions associated with carcinoma invasion in breast tissue. The signals through various nuclear receptors, especially estrogen‐related receptor‐α in carcinoma cells and liver receptor homologue‐1 in adipocytes adjacent to carcinoma invasion, in conjunction with various cytokines and/or growth factors, play pivotal roles in this induction of intra‐tumoral aromatase. This increased aromatase subsequently results in increased in situ estrogen concentrations of breast cancer. Aromatase inhibitors are currently established as the gold standard for the treatment for ER‐positive breast carcinoma but resistance to the therapy still remains to be solved by other modes of suppression of intra‐tumoral estrogen production.
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