STAT3 Stabilizes IKKα Protein through Direct Interaction in Transformed and Cancerous Human Breast Epithelial Cells

Signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) are two representative transcription factors that play a critical role in inflammation-associated tumorigenesis through multi-level cooperation. Unlike other types of tumors, breast carcinomas have shown a significant dependency on the non-classical NF-κB pathway as well as the classical one. The α subunit of the inhibitor of the κB kinase (IKK) complex, IKKα, is involved in both classical and non-classical activation of NF-κB. Although the cross-talk between STAT3 and NF-κB has been suggested in several studies, the interplay between STAT3 and the regulators of NF-κB including IKKα has not been fully clarified yet. In this study, we observed overexpression and co-localization of IKKα and STAT3 in human breast cancer tissues as well as in H-Ras transformed human breast epithelial (H-Ras MCF-10A) and breast cancer (MDA-MB-231) cells. By utilizing small interfering RNA (siRNA) technology, we were able to demonstrate that STAT3 up-regulated IKKα, but not IKKβ or IKKγ, in these cells. This was attributable to direct binding to and subsequent stabilization of IKKα protein by blocking the ubiquitin-proteasome system. Notably, we identified the lysine 44 residue of IKKα as a putative binding site for STAT3. Moreover, siRNA knockdown of IKKα attenuated viability, anchorage-independent growth and migratory capabilities of H-Ras MCF-10A cells. Taken together, these findings propose a novel mechanism responsible for NF-κB activation by STAT3 through stabilization of IKKα, which contributes to breast cancer promotion and progression. Thus, breaking the STAT3-IKKα alliance can be an alternative therapeutic strategy for the treatment of breast cancer.ope

ERK Dephosphorylation Through MKP1 Deacetylation by SIRT1 Attenuates RAS-Driven Tumorigenesis

The role of Situin 1 (SIRT1) in tumorigenesis is still controversial due to its wide range of substrates, including both oncoproteins and tumor suppressors. A recent study has demonstrated that SIRT1 interferes in the Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven activation of the Raf-mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway, thereby inhibiting tumorigenesis. However, the molecular mechanism of SIRT1 as a tumor suppressor in RAS-driven tumorigenesis has been less clearly determined. This study presents evidence that the ectopic expression of SIRT1 attenuates RAS- or MEK-driven ERK activation and reduces cellular proliferation and transformation in vitro. The attenuation of ERK activation by SIRT1 results from prompt dephosphorylation of ERK, while MEK activity remains unchanged. We identified that MKP1, a dual specific phosphatase for MAPK, was deacetylated by SIRT1. Deacetylation of MKP1 by direct interaction with SIRT1 increased the binding affinity to ERK which in turn facilitated inactivation of ERK. Taken together, these results suggest that SIRT1 would act as a tumor suppressor by modulating RAS-driven ERK activity through MKP1 deacetylation.ope

IKKα-deficient lung adenocarcinomas generate an immunosuppressive microenvironment by overproducing Treg-inducing cytokines

The tumor microenvironment (TME) provides potential targets for cancer therapy. However, how signals originating in cancer cells affect tumor-directed immunity is largely unknown. Deletions in the CHUK locus, coding for IκB kinase α (IKKα), correlate with reduced lung adenocarcinoma (ADC) patient survival and promote KrasG12D-initiated ADC development in mice, but it is unknown how reduced IKKα expression affects the TME. Here, we report that low IKKα expression in human and mouse lung ADC cells correlates with increased monocyte-derived macrophage and regulatory T cell (Treg) scores and elevated transcription of genes coding for macrophage-recruiting and Treg-inducing cytokines (CSF1, CCL22, TNF, and IL-23A). By stimulating recruitment of monocyte-derived macrophages from the bone marrow and enforcing a TNF/TNFR2/c-Rel signaling cascade that stimulates Treg generation, these cytokines promote lung ADC progression. Depletion of TNFR2, c-Rel, or TNF in CD4+ T cells or monocyte-derived macrophages dampens Treg generation and lung tumorigenesis. Treg depletion also attenuates carcinogenesis. In conclusion, reduced cancer cell IKKα activity enhances formation of a protumorigenic TME through a pathway whose constituents may serve as therapeutic targets for KRAS-initiated lung ADC.ope

Macrophage inducible nitric oxide synthase circulates inflammation and promotes lung carcinogenesis

Human lung squamous cell carcinoma (SCC) is highly associated with increased pulmonary macrophage infiltration. Previously, we showed that marked pulmonary infiltrating macrophages were required for spontaneous lung SCC development in a mouse model (L-IkkαKA/KA , KA/KA) that resembles human lung SCC. Interestingly the lung SCC-associated macrophages specifically express elevated inducible nitric oxide synthase (NOS2). However, the role of macrophage NOS2 in lung carcinogenesis has not been explored. Here, we show that NOS2 ablation inhibits macrophage infiltration, fibrosis, and SCC development in the lungs of KA/KA mice. Macrophage NOS2 was found to circulate inflammation and enhance macrophage migration and survival. NOS2 promotes foamy macrophage formation characterized with impaired lipid metabolism. NOS2 null bone marrow transplantation reduces foamy macrophage numbers and carcinogenesis in KA/KA chimaeras. This finding sheds light on a new mechanism by which macrophage NOS2 increases pulmonary inflammatory responses and macrophage survival and impairs macrophage lipid metabolism, thereby promoting lung SCC formation.ope

JNK-mediated Ser27 phosphorylation and stabilization of SIRT1 promote growth and progression of colon cancer through deacetylation-dependent activation of Snail

Sirtuin 1 (SIRT1), an NAD+ -dependent histone/protein deacetylase, has multifaceted functions in various biological events such as inflammation, aging, and energy metabolism. The role of SIRT1 in carcinogenesis, however, is still under debate. Recent studies have indicated that aberrant overexpression of SIRT1 is correlated with metastasis and poor prognosis in several types of malignancy, including colorectal cancer. In the present study, we found that both SIRT1 and SIRT1 phosphorylated on serine 27 were coordinately upregulated in colon cancer patients' tissues and human colon cancer cell lines. This prompted us to investigate a role of phospho-SIRT1 in the context of colon cancer progression. A phosphorylation-defective mutant form of SIRT1, in which serine 27 was substituted by alanine (SIRT1-S27A), exhibited lower protein stability compared to that of wild-type SIRT1. Notably, human colon cancer (HCT-116) cells harboring the SIRT1-S27A mutation showed decreased cell proliferation and reduced capability to form xenograft tumor in athymic nude mice, which was accompanied by diminished transcriptional activity of Snail. HCT-116 cells carrying SIRT1-S27A were less capable of deacetylating the Snail protein, with a concomitant decrease in the levels of interleukin (IL)-6 and IL-8 mRNA transcripts. Taken together, these observations suggest that SIRT1 stabilized through phosphorylation on serine 27 exerts oncogenic effects at least partly through deacetylation-dependent activation of Snail and subsequent transcription of IL-6 and IL-8 in human colon cancer cells.ope

Oral-Gut Microbiome Axis in Gastrointestinal Disease and Cancer

It is well-known that microbiota dysbiosis is closely associated with numerous diseases in the human body. The oral cavity and gut are the two largest microbial habitats, playing a major role in microbiome-associated diseases. Even though the oral cavity and gut are continuous regions connected through the gastrointestinal tract, the oral and gut microbiome profiles are well-segregated due to the oral-gut barrier. However, the oral microbiota can translocate to the intestinal mucosa in conditions of the oral-gut barrier dysfunction. Inversely, the gut-to-oral microbial transmission occurs as well in inter- and intrapersonal manners. Recently, it has been reported that oral and gut microbiomes interdependently regulate physiological functions and pathological processes. Oral-to-gut and gut-to-oral microbial transmissions can shape and/or reshape the microbial ecosystem in both habitats, eventually modulating pathogenesis of disease. However, the oral-gut microbial interaction in pathogenesis has been underappreciated to date. Here, we will highlight the oral-gut microbiome crosstalk and its implications in the pathogenesis of the gastrointestinal disease and cancer. Better understanding the role of the oral-gut microbiome axis in pathogenesis will be advantageous for precise diagnosis/prognosis and effective treatment.ope

Chemerin Treatment Inhibits the Growth and Bone Invasion of Breast Cancer Cells

Chemerin is secreted as prochemerin from various cell types and then cleaved into the bioactive isoform by specific proteases. In various cancer types, chemerin exhibits pro- or antitumor effects. In the present study, chemerin treatment significantly inhibited the viability and invasion of breast cancer cells in the absence or presence of transforming growth factor (TGF)-β and insulin-like growth factor (IGF)-1. The expression levels of E-cadherin and vimentin were reduced in chemerin-treated breast cancer cells. However, chemerin treatment recovered the reduced E-cadherin expression level in breast cancer cells treated with TGF-β or IGF-1. Chemerin treatment inhibited nuclear β-catenin levels in breast cancer cells stimulated with or without TGF-β or IGF-1. In addition, chemerin treatment blocked the increase in the receptor activator of nuclear factor kappa-Β ligand (RANKL)/osteoprotegerin (OPG) ratio in osteoblastic cells exposed to metastatic breast cancer cell-derived conditioned medium. Chemerin treatment inhibited RANKL-induced osteoclast formation and bone resorption by reducing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K. Intraperitoneal administration of chemerin inhibited tumor growth in MCF-7 breast cancer cell-injected mice and reduced the development of osteolytic lesions resulting from intratibial inoculation of MDA-MB-231 cells. Taken together, chemerin inhibits the growth and invasion of breast cancer cells and prevents bone loss resulting from breast cancer cells by inhibiting finally osteoclast formation and activity.ope

Direct Contact with Platelets Induces Podoplanin Expression and Invasion in Human Oral Squamous Cell Carcinoma Cells

Oral squamous cell carcinoma (OSCC) is mostly diagnosed at an advanced stage, with local and/or distal metastasis. Thus, locoregional and/or local control of the primary tumor is crucial for a better prognosis in patients with OSCC. Platelets have long been considered major players in cancer metastasis. Traditional antiplatelet agents, such as aspirin, are thought to be potential chemotherapeutics, but they need to be used with caution because of the increased bleeding risk. Podoplanin (PDPN)-expressing cancer cells can activate platelets and promote OSCC metastasis. However, the reciprocal effect of platelets on PDPN expression in OSCC has not been investigated. In this study, we found that direct contact with platelets upregulated PDPN and integrin β1 at the protein level and promoted invasiveness of human OSCC Ca9.22 cells that express low levels of PDPN. In another human OSCC HSC3 cell line that express PDPN at an abundant level, silencing of the PDPN gene reduced cell invasiveness. Analysis of the public database further supported the co-expression of PDPN and integrin β1 and their increased expression in metastatic tissues compared to normal and tumor tissues of the oral cavity. Taken together, these data suggest that PDPN is a potential target to regulate platelet-tumor interaction and metastasis for OSCC treatment, which can overcome the limitations of traditional antiplatelet drugs.ope

Platelet CLEC2-Podoplanin Axis as a Promising Target for Oral Cancer Treatment

Cancer tissues are not just simple masses of malignant cells, but rather complex and heterogeneous collections of cellular and even non-cellular components, such as endothelial cells, stromal cells, immune cells, and collagens, referred to as tumor microenvironment (TME). These multiple players in the TME develop dynamic interactions with each other, which determines the characteristics of the tumor. Platelets are the smallest cells in the bloodstream and primarily regulate blood coagulation and hemostasis. Notably, cancer patients often show thrombocytosis, a status of an increased platelet number in the bloodstream, as well as the platelet infiltration into the tumor stroma, which contributes to cancer promotion and progression. Thus, platelets function as one of the important stromal components in the TME, emerging as a promising chemotherapeutic target. However, the use of traditional antiplatelet agents, such as aspirin, has limitations mainly due to increased bleeding complications. This requires to implement new strategies to target platelets for anti-cancer effects. In oral squamous cell carcinoma (OSCC) patients, both high platelet counts and low tumor-stromal ratio (high stroma) are strongly correlated with increased metastasis and poor prognosis. OSCC tends to invade adjacent tissues and bones and spread to the lymph nodes for distant metastasis, which is a huge hurdle for OSCC treatment in spite of relatively easy access for visual examination of precancerous lesions in the oral cavity. Therefore, locoregional control of the primary tumor is crucial for OSCC treatment. Similar to thrombocytosis, higher expression of podoplanin (PDPN) has been suggested as a predictive marker for higher frequency of lymph node metastasis of OSCC. Cumulative evidence supports that platelets can directly interact with PDPN-expressing cancer cells via C-type lectin-like receptor 2 (CLEC2), contributing to cancer cell invasion and metastasis. Thus, the platelet CLEC2-PDPN axis could be a pinpoint target to inhibit interaction between platelets and OSCC, avoiding undesirable side effects. Here, we will review the role of platelets in cancer, particularly focusing on CLEC2-PDPN interaction, and will assess their potentials as therapeutic targets for OSCC treatment.ope

A study on the factors influencing career commitment of married working women

현대 우리 사회에서 맞벌이 부부가 보편적인 가정의 모습으로 자리 잡아 가고 있음에도 불구하고 여전히 여성은 직업 활동에도 남편, 가정, 사회로부터 전통적 성 역할 태도를 요구 받으며 가사 일을 병행해야 하는 이중적인 부담에 시달리는 모순에 처해있다. 이러한 상황은 기혼 여성의 직업 생활을 방해하고, 나아가 여성을 노동시장에서 이탈하게 하는 원인이 된다. 이에 본 연구에서는 직업에 대한 심리적 애착과 직업을 지속하기 위한 노력으로 경력몰입을 개념화하고 기혼취업여성이 그들의 경력이 중단되지 않고 직업을 지속하는 데 어떠한 요인들이 영향을 미치는지를 살펴보는 것을 목적으로 한다. 본 연구에서는 기혼취업여성의 경력몰입에 영향을 미치는 요인을 인구사회학적 요인, 심리 요인, 직업 요인, 가족 요인으로 파악하고 이들의 차별적 영향력을 검증하였다. 연구를 위해 대기업, 중소기업, 금융기관, 학교 등에 종사하는 기혼취업여성 387명을 대상으로 경력몰입, 직업정체성, 셀프리더십, 직업만족도 및 일-가족 다중역할 갈등에 대한 온라인 설문조사를 실시하였다. 연구문제와 그에 대한 연구결과는 다음과 같다. 첫째, 기혼취업여성들의 경력몰입과 그와 관련된 변인의 경향성을 살펴본 결과, 직업만족도, 셀프리더십, 직업정체성, 경력몰입 모두 보통 이상의 비교적 원만한 수준을 나타내었고, 일-가족 다중역할 갈등은 보통을 약간 상회하는 수준으로 경험하고 있는 것으로 나타났다. 변수 간 상관관계에서는 교육수준, 현 직업에서의 종사기간, 월 평균 가구소득, 직업정체성, 셀프리더십, 직업만족도의 경우 경력몰입과 유의한 정적 상관관계를 나타내었고, 일-가족 다중역할 갈등은 경력몰입과 유의한 부적 상관관계를 가진 것으로 나타났다. 둘째, 인구사회학적 요인에 따라 기혼 취업 여성의 경력몰입에 어떠한 차이가 있는지 확인한 결과, 직업 분류 요인에서는 관리자와 전문직 종사자가 사무직, 서비스직 종사자보다 경력몰입 수준이 높은 것으로 나타났으며, 고용형태 요인에서는 고용주·자영업자가 경력몰입 수준이 더 높은 것으로 나타났다. 자녀 요인에서는 자녀가 있는 경우 경력몰입 수준이 더 높다는 결과를 보였는데, 이는 유자녀 기혼여성은 남성과 마찬가지로 양육비, 교육비 등의 지출에 대한 책임과 부담감을 가지고 더욱 경력에 대한 몰입을 증가시키는 것으로 설명할 수 있다. 셋째, 기혼취업여성의 관련 변인들이 경력몰입에 미치는 상대적 영향력을 확인하기 위해 위계적 회귀분석을 실시하였다. 그 결과, 전체 요인들을 투입했을 때 경력몰입을 40% 설명하였으며, 투입 요인 중 직업정체성이 가장 큰 영향을 미치는 것으로 나타났다. 가족 요인 측면에서 일-가족 다중역할 갈등이 경력몰입에 부적 영향을 미치는 것으로 나타났으며, 직업 요인 측면에서 직업만족도가 경력몰입에 정적인 영향을 미쳤다. 마지막으로 심리 요인 측면에서는 직업정체성과 셀프리더십 모두 정적인 영향을 미치는 것으로 나타났다. 본 연구는 기혼취업여성의 경력몰입에 영향을 미치는 변인을 탐색하였다. 기혼여성의 진로 성취 과정에서 양육 및 가사노동을 비롯한 가정생활을 조화롭게 영위하면서도 자신의 삶에 대한 질적인 개선을 위한 여성 진로 상담 개입 방안을 마련함에 있어서 시사점을 제공한다.;Today, double-income families have become universal in our society. Nevertheless, working women are still forced to play traditional gender roles by husband, family, and society and face dual burdens of working and of housekeeping. The circumstance impedes married women’s career life and ends up making women leave the labor market. Therefore, the purpose of this study is to conceptualize career commitment which is psychological attachment for jobs and an effort to keep working, and find the factors that influence married working women’s job continuity without career discontinuity. This study found that the factors influencing career commitment of married working women were social demographic factor, psychological factor, job factor, and family factor, and examine the differentiated influence of each one. The study subjects were 387 married women working in large companies, small and medium businesses, financial institutions, and schools. They participated in the online questionnaire survey about career commitment, occupational identity, self-leadership, occupational satisfaction, and work-family multiple role conflict. The study issues and results are presented as follows: First, career commitment of married working women and inclination of relevant variables were analyzed. As a result, occupational satisfaction, self-leadership, occupational identity, and career commitment had a relatively acceptable level higher than a middle level. Work-family multiple role conflict had a little higher level than a middle level. With regard to the correlation between variables, occupational identity, self-leadership, and occupational satisfaction had the significantly positive correlation with career commitment, and work-family multiple role conflict had the significantly negative correlation with career commitment. Secondly, the difference in career commitment of married working women was analyzed according to social demographic factors. As a result, the higher education they had, the more they worked as manager and expert, and the higher family income they had, the higher a level of career commitment was. This study revealed that when they had a child, a level of career commitment was high. It indicates that married working women with a child have as many responsibilities and burdens of child-rearing cost and education cost as their husbands, and consequently commit themselves more to career. Meanwhile, age, career years, their income, their spouse’s child-caring hours didn’t show significant difference in terms of the influence on career commitment. Thirdly, to find the relative influence of married working women’s relevant variables on career commitment, hierarchical regression analysis was conducted. As a result, when all factors were injected, career comment had 40% of explanatory power. Among the injected factors, occupational identity was the most influential. From the perspective of psychological factors, occupational identity and self-leadership were positively influential. From the perspective of job factors, occupational satisfaction positively influenced career commitment. From the perspective of family factors, work-family multiple role conflict negatively influenced career commitment. This study explored the variables that influenced career commitment of married working women. This study made a suggestion for preparing a consulting intervention plan for women’s career, which is aimed at harmonizing married women’s child-rearing and household labor in the process of their career achievement and improving their quality of life.Ⅰ. 서론 1 A. 연구의 필요성 및 목적 1 B. 연구문제 3 C. 용어의 정의 4 Ⅱ. 이론적 배경 6 A. 기혼취업여성의 경력몰입 6 1. 기혼취업여성의 취업특성 6 2. 기혼취업여성의 경력몰입 7 B. 기혼취업여성의 경력몰입에 영향을 미치는 요인 10 1. 심리 요인 11 2. 직업 요인 19 3. 가족 요인 23 Ⅲ. 연구방법 27 A. 연구대상 및 자료수집 27 B. 측정도구 27 C. 자료 분석 33 Ⅳ. 연구결과 34 A. 자료의 기초분석 34 1. 연구대상의 일반적 특성 34 2. 주요 변수에 대한 기술적 통계치 36 B. 기혼취업여성의 경력몰입 영향요인 37 1. 변수 간 상관관계 분석 37 2. 경력몰입의 차이검증 40 3. 기혼취업여성의 경력몰입에 미치는 영향요인 분석 42 Ⅴ. 논의 및 제언 46 A. 요약 및 논의 46 B. 연구의 제한점 및 제언 52 참고문헌 53 부록 64 ABSTRACT 7