Association between the COVID-19 pandemic and childhood development aged 30 to 36 months in South Korea, based on the National health screening program for infants and children database.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on the neurodevelopment of children. However, the precise effects of the virus and the social consequences of the pandemic on pediatric neurodevelopment are not yet fully understood. We aimed to compare the neurodevelopment of children between before and during the COVID-19 pandemic, as well as examine the impact of socioeconomic status (SES) and regional differences on the development. METHODS: The study used the Korean Developmental Screening Test to compare the difference in the risk of neurodevelopmental delay between before and during the COVID-19 pandemic. Multivariable logistic regression analysis was conducted to identify the relationship between experiencing the COVID-19 pandemic and the risk of neurodevelopmental delay. Stratified analyses were performed to determine whether the developmental delays caused by the pandemic's impact varied depending on SES or regional inequality. RESULTS: This study found an association between the experience of COVID-19 and a higher risk of neurodevelopmental delay in communication (adjusted OR [aOR]: 1.21, 95% confidence interval [CI]: 1.19, 1.22; P-value: < 0.0001) and social interaction (aOR: 1.15, 95% CI: 1.13, 1.17; P-value: < 0.0001) domains among children of 30-36 months' ages. Notably, the observed association in the Medicaid group of children indicates a higher risk of neurodevelopmental delay compared to those in the non-Medicaid group. CONCLUSIONS: These findings highlight the need to be concerned about the neurodevelopment of children who experienced the COVID-19 pandemic. The study also calls for increased training and support for Medicaid children, parents, teachers, and healthcare practitioners. Additionally, policy programs focused on groups vulnerable to developmental delays are required.

Risk factors for critical COVID-19 illness during Delta- and Omicron-predominant period in Korea; using K-COV-N cohort in the National health insurance service.

BACKGROUND: This study evaluated the clinical characteristics of patients with COVID-19 in Korea, and examined the relationship between severe COVID-19 cases and underlying health conditions during the Delta (September 20, 2021 to December 4, 2021) and the Omicron (February 20, 2022 to March 31, 2022) predominant period. METHODS: This study assessed the association between critical COVID-19 illness and various risk factors, including a variety of underlying health conditions, using multiple logistic regression models based on the K-COV-N cohort, a nationwide data of confirmed COVID-19 cases linked with COVID-19 vaccination status and the National Health Insurance claim information. RESULTS: We analyzed 137,532 and 8,294,249 cases of COVID-19 infection during the Delta and the Omicron variant dominant periods, respectively. During the Delta as well as the Omicron period, old age (≥80 years) showed the largest effect size among risk factors for critical COVID-19 illness (aOR = 18.08; 95% confidence interval [CI] = 14.71-22.23 for the Delta; aOR = 24.07; 95% CI = 19.03-30.44 for the Omicron period). We found that patients with solid organ transplant (SOT) recipients, unvaccinated, and interstitial lung disease had more than a two-fold increased risk of critical COVID-19 outcomes between the Delta and Omicron periods. However, risk factors such as urban residence, underweight, and underlying medical conditions, including chronic cardiac diseases, immunodeficiency, and mental disorders, had different effects on the development of critical COVID-19 illness between the Delta and Omicron periods. CONCLUSION: We found that the severity of COVID-19 infection was much higher for the Delta variant than for the Omicron. Although the Delta and the Omicron variant shared many risk factors for critical illness, several risk factors were found to have different effects on the development of critical COVID-19 illness between those two variants. Close monitoring of a wide range of risk factors for critical illness is warranted as new variants continue to emerge during the pandemic.

The homeoprotein HOXB2 limits triple-negative breast carcinogenesis via extracellular matrix remodeling.

Homeobox genes and their encoded DNA-binding homeoproteins are master regulators of development. Consequently, these homeotic elements may regulate key steps in cancer pathogenesis. Here, using a combination of in silico analyses of large-scale patient datasets, in vitro RNAi phenotyping, and in vivo validation studies, we investigated the role of HOXB2 in different molecular subtypes of human breast cancer (BC). The gene expression signatures of HOXB2 are different across distinct BC subtypes due to various genetic alterations, but HOXB2 was specifically downregulated in the aggressive triple-negative subtype (TNBC). We found that the reduced expression of HOXB2 was correlated with the metastatic abilities (epithelial-to-mesenchymal transition) of TNBC cells. Further, we revealed that HOXB2 restrained TNBC aggressiveness by ECM organization. HOXB2 bound to the promoter regions of MATN3 and ECM2 and regulated their transcription levels. Forced expression of HOXB2 effectively prevented TNBC progression and metastasis in a mouse xenograft model. Reduction of HOXB2 and the HOXB2/MATN3/ECM2 transcriptional axis correlated with poor survival in patients with various cancers. Further, we found the long non-coding RNA HOXB-AS1 in complex with SMYD3, a lysine methyltransferase, as an epigenetic switch controlling HOXB2 expression. Overall, our results indicate a tumor-suppressive role of HOXB2 by maintaining ECM organization and delineate potential clinical utility of HOXB2 as a marker for TNBC patients.

Risk Factors for Severe and Critical Coronavirus Disease 2019 in Children.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is generally mild in children; however, severe or critical cases may occur. In this nationwide study, we analyzed clinical manifestations in children diagnosed with severe acute respiratory syndrome coronavirus 2 to identify high-risk groups for severe or critical disease and compared the clinical features between the Delta- and Omicron-dominant periods. METHODS: Data were retrieved from the National Health Insurance Service (NHIS) database and merged with the Korea Disease Control and Prevention Agency-COVID-19-NHIS cohort, which includes information on COVID-19 cases and vaccination records. We included individuals <20 years old diagnosed with COVID-19 during both periods (Delta: July 25, 2021-January 15, 2022; Omicron: January 16, 2022-March 31, 2022). RESULTS: Proportion of severe or critical cases was higher during the Delta period than during the Omicron period. The Omicron period saw increased hospitalization for pneumonia and croup and increased likelihood of hospitalization for neurological manifestations. The risk of severe COVID-19 depended on age group (Delta: highest for 12-19 years; Omicron: 0-4 years). This risk was high in children with multiple complex chronic conditions during both periods and with obesity or asthma during the Delta but not during the Omicron period. Two-dose COVID-19 vaccination provided strong protection against severe disease in the Delta period (adjusted odds ratio: 0.20), with reduced effectiveness in the Omicron period (adjusted odds ratio: 0.91). However, it significantly reduced the risk of critical illness (adjusted odds ratio: 0.14). CONCLUSIONS: These findings can facilitate identification of children at high risk of severe or critical COVID-19, who may require intensive medical support, and development of vaccination policies.

Women's Employment in Industries and Risk of Preeclampsia and Gestational Diabetes: A National Population Study of Republic of Korea.

Background: Some working conditions may pose a higher physical or psychological demand to pregnant women leading to increased risks of pregnancy complications. Objectives: We assessed the association of woman's employment status and the industrial classification with obstetric complications. Methods: We conducted a national population study using the National Health Information Service database of Republic of Korea. Our analysis encompassed 1,316,310 women who experienced first-order live births in 2010-2019. We collected data on the employment status and the industrial classification of women, as well as their diagnoses of preeclampsia (PE) and gestational diabetes mellitus (GDM) classified as A1 (well controlled by diet) or A2 (requiring medication). We calculated odds ratios (aORs) of complications per employment, and each industrial classification was adjusted for individual risk factors. Results: Most (64.7%) were in employment during pregnancy. Manufacturing (16.4%) and the health and social (16.2%) work represented the most prevalent industries. The health and social work exhibited a higher risk of PE (aOR = 1.11, 95% confidence interval [CI]: 1.03-1.21), while the manufacturing industry demonstrated a higher risk of class A2 GDM (1.20, 95% CI: 1.03-1.41) than financial intermediation. When analyzing both classes of GDM, women who worked in public administration and defense/social security showed higher risk of class A1 GDM (1.04, 95% CI: 1.01, 1.07). When comparing high-risk industries with nonemployment, the health and social work showed a comparable risk of PE (1.02, 95% CI: 0.97, 1.07). Conclusion: Employment was associated with overall lower risks of obstetric complications. Health and social service work can counteract the healthy worker effect in relation to PE. This highlights the importance of further elucidating specific occupational risk factors within the high-risk industries.

Regulation of sexually dimorphic placental adaptation in LPS exposure-induced intrauterine growth restriction.

BACKGROUND: Sexual dimorphism in placental physiology affects the functionality of placental adaptation during adverse pregnancy. Defects of placental function compromise fetal programming, affecting the offspring's adult life. However, studies focusing on the relationship between sex-specific placental adaptation and consequent fetal maldevelopment under sub-optimal uterus milieu are still elusive. METHODS: Here, we investigated the effects of maternal lipopolysaccharide (LPS) exposure between placental sex. Pregnant ICR mice received intraperitoneal injection of phosphate-buffered saline or 100, 200, and 400 µg/kg LPS on the gestational day (GD) 15.5. To determine whether prenatal maternal LPS exposure resulted in complicated pregnancy outcomes, survival rate of embryos was calculated and the growth of embryos and placentas was examined. To elucidate global transcriptomic changes occurring in the placenta, total RNA-sequencing (RNA-seq) was performed in female and male placentas. RESULTS: LPS administration induced placental inflammation in both sexes at GD 17.5. Prenatal infection resulted in growth retardation in both sexes of embryos, and especially more prevalently in male. Impaired placental development was observed in a sex-specific manner. LPS 400 µg/kg reduced the percentage area of the labyrinth in females and junctional zone in males, respectively. RNA-sequencing revealed widespread sexually dimorphic transcriptional changes in placenta. In particular, representative changes were involved in biological processes such as trophoblast differentiation, nutrient/ion transporter, pregnancy, and immune system. CONCLUSIONS: Our results present the sexually dimorphic responses of placental physiology in intrauterine growth restriction model and provide tentative relationship further to be elucidated between sex-biased placental functional change and long-term effects on the offspring's later life.

Trend of Women's Health Research in Korea, 2012-2020: Topic and Text Network Analysis.

BACKGROUND: With the epidemiological transition, sociodemographic changes and differential lifetime experiences of women, women's health research improves knowledge of diverse health issues and the impact of policies. To explore the initiatives of women's health research in Korea, the present study examined the trends and topics of research on women's health funded by the government. METHODS: We searched all research projects on women's health funded by the government between 2012 and 2020 in Korea using the National Science & Technology Information Service database. We reviewed all the titles and abstract of the projects and examined the research trends by year. Content analysis was performed using both deductive and inductive approaches. Text network analysis and visualization by topic were conducted for keywords with a minimum of 10 occurrences in the title and abstract. RESULTS: Total number and funding amount of research projects on women's health in 2020 increased by 2.4 and 2.2 times over 2012 levels, respectively. The Ministry of Health and Welfare and the Ministry of Food and Drug Safety funded 20.9% of all projects. The majority of the topics (59.8%) addressed breast and gynecological cancers. Those on sexual and reproductive health accounted for 16.7%, with steep growth in the number (6.1 times) and funding (11.1 times) over 2012 levels. The topic analysis presented a more complex keyword network in 2020 than in 2012; however, the keywords frequently used in 2020 were similar to those of 2012. CONCLUSION: Women's health research projects have been growing in number and funding, with limited diversity in topics. Diversifying the topics and focusing on issues beyond the breast and pregnancy would be needed to reflect the complete life course of women. Institutionalization of diverse communication channels with various interest groups for women's health would be needed to better understand women's health needs from a public health perspective.

Unequal burdens of COVID-19 infection: a nationwide cohort study of COVID-19-related health inequalities in Korea.

OBJECTIVES: While the Korean government's response to the coronavirus disease 2019 (COVID-19) pandemic is considered effective given the relatively low mortality rate, issues of inequality have been insufficiently addressed. This study explored COVID-19-related health inequalities in Korea. METHODS: Age standardization for various health inequality indices was derived using data from the Korean National Health Insurance Service, the Korea Disease Control and Prevention Agency, and the Microdata Integrated Service of Statistics Korea. The slope index of inequality (SII) and relative index of inequality (RII) were calculated for socioeconomic variables, while absolute difference (AD) and relative difference (RD) were used for gender and disability inequalities. RESULTS: We observed a number of COVID-19-related health outcome inequalities. Gender inequality was particularly noticeable in infection rates, with the rate of women 1.16 times higher than that of men. In contrast, socioeconomic inequality was evident in vaccination rates, with a 4.5-fold (SII, -4.519; 95% confidence interval, -7.403 to -1.634) difference between the highest and lowest household income groups. Regarding clinical progression post-infection, consistent findings indicated higher risk for men (RD for hospitalization, 0.90; severe cases, 0.54; and fatality, 0.65), individuals with disabilities (RD for hospitalization, 2.27; severe cases, 2.29; and fatality, 2.37), and those from lower socioeconomic groups (SII for hospitalization, 1.778; severe cases, 0.089; and fatality, 0.451). CONCLUSIONS: While the infection risk was nearly ubiquitous, not everyone faced the same level of risk post-infection. To prevent further health inequalities, it is crucial to develop a thoughtful policy acknowledging individual health conditions and resources.

Did the socioeconomic inequalities in avoidable and unavoidable mortality worsen during the first year of the COVID-19 pandemic in Korea?

OBJECTIVES: This study examined changes in socioeconomic inequalities in mortality in Korea before and after the outbreak of coronavirus disease 2019 (COVID-19). METHODS: From 2017 to 2020, age-standardized mortality rates were calculated for all-cause deaths, avoidable deaths (preventable deaths, treatable deaths), and unavoidable deaths using National Health Insurance claims data and Statistics Korea's cause of death data. In addition, the slope index of inequality (SII) and the relative index of inequality (RII) by six income levels (Medical Aid beneficiary group and quintile of health insurance premiums) were computed to analyze the magnitude and change of mortality inequalities. RESULTS: All-cause and avoidable mortality rates decreased steadily between 2017 and 2020, whereas unavoidable mortality remained relatively stable. In the case of mortality inequalities, the disparity in all-cause mortality between income classes was exacerbated in 2020 compared to 2019, with the SII increasing from 185.44 to 189.22 and the RII increasing from 3.99 to 4.29. In particular, the preventable and unavoidable mortality rates showed an apparent increase in inequality, as both the SII (preventable: 91.31 to 92.01, unavoidable: 69.99 to 75.38) and RII (preventable: 3.42 to 3.66, unavoidable: 5.02 to 5.89) increased. CONCLUSIONS: In the first year of the COVID-19 pandemic, mortality inequality continued to increase, although there was no sign of exacerbation. It is necessary to continuously evaluate mortality inequalities, particularly for preventable and unavoidable deaths.

Does the father's job matter? Parental occupation and preterm birth in Korea.

OBJECTIVES: Limited evidence is available regarding the impact of paternal occupation and its combined effect with maternal occupation on preterm birth. Therefore, we assessed the association of maternal and paternal occupations with preterm birth. METHODS: We used the national birth data of Korea between 2010 and 2020. Parental occupations were divided into 5 categories: (1) managers; (2) professionals, technicians, and related workers; (3) clerks and support workers; (4) service and sales workers; and (5) manual workers. A multinomial logistic regression model was used to calculate the adjusted odds ratios (aORs) of extremely, very, and moderate-to-late preterm births per occupational category considering individual risk factors. RESULTS: For the 4,004,976 singleton births, 40.2% of mothers and 95.5% of fathers were employed. Compared to non-employment, employment was associated with a lower risk of preterm birth. Among employed mothers, service and sales occupations were associated with a higher risk of preterm birth than managerial occupations (aOR, 1.06; 95% confidence interval [CI], 1.01 to 1.10 for moderate-to-late preterm births). The father's manual occupation was associated with a higher risk of preterm birth (aOR, 1.09; 95% CI, 1.05 to 1.13 for moderate-to-late preterm) than managerial occupations. When both parents had high-risk occupations, the risk of preterm birth was higher than in cases where only the mother or neither of the parents had a high-risk occupation. CONCLUSIONS: Paternal occupation was associated with preterm birth regardless of maternal employment and occupation and modified the effect of maternal occupation. Detailed occupational environment data are needed to identify the paternal exposures that increase the risk.

Risk of adverse pregnancy outcomes by maternal occupational status: A national population-based study in South Korea.

OBJECTIVE: This study examined the association between maternal occupational status and adverse pregnancy outcomes in the general South Korean population. METHODS: We analyzed 1 825 845 employed and non-employed women with a diagnostic code for pregnancy in the National Health Insurance Service (NHIS) database (2010-2019) of South Korea. Based on their employment status and type of occupation, we calculated risk ratios for three adverse outcomes: early abortive outcomes (miscarriage, ectopic pregnancy, and molar pregnancy), stillbirth, and no live birth (diagnosis of pregnancy with no record of live birth thereafter, which include early abortive outcomes and stillbirth) with adjusting for covariates. RESULTS: Overall, 18.0%, 0.7%, and 39.8% ended in early abortive outcomes, stillbirths, and no live births, respectively. The risk of early abortive outcomes and stillbirths was higher in non-employed women than in employed women, while no live births were more frequent in employed women. Those in the health and social work industry showed the highest risk of no live births. Manufacturing jobs (1.030, 95% CI: 1.013, 1.047) and health/social work (1.029, 95% CI: 1.012, 1.046) were associated with an increased risk of early abortive outcomes compared with financial and insurance jobs. Consistently higher risks of no live births were observed in the manufacturing, wholesale/retail trade, education, health/social work, and public/social/personal service occupation. CONCLUSION: Employment during pregnancy and several occupation types were associated with a higher risk of pregnancy loss. Additional research using detailed job activity data is needed to determine specific occupational causes of adverse pregnancy outcomes.

FOXM1 Inhibition Enhances the Therapeutic Outcome of Lung Cancer Immunotherapy by Modulating PD-L1 Expression and Cell Proliferation.

Programmed death-ligand 1 (PD-L1) is a major target to cancer immunotherapy, and anti-PD-L1 and anti-PD-1 antibody-mediated immunotherapy are being increasingly used. However, immune checkpoint inhibitors (ICIs) are ineffective in treating large tumors and cause various immune-related adverse events in nontarget organs, including life-threatening cardiotoxicity. Therefore, the development of new therapeutic strategies to overcome these limitations is crucial. The focus of this study is the forkhead box protein M1 (FOXM1), which is identified as a potential therapeutic target for cancer immunotherapy and is associated with the modulation of PD-L1 expression. Selective small interfering RNA knockdown of FOXM1 or treatment with thiostrepton (TST) significantly reduces PD-L1 expression in non-small-cell lung cancer (NSCLC) cells and inhibits proliferation. Chromatin immunoprecipitation-PCR reveals that FOXM1 selectively upregulates PD-L1 expression by binding directly to the PD-L1 promoter. In vivo animal studies have shown that TST treatment significantly downregulates PD-L1 expression in human NSCLC tumors, while greatly reducing tumor size without side effects on normal tissues. Combined treatment with TST and anti-4-1BB antibody in the LLC-1 syngeneic tumor model induces synergistic therapeutic outcomes against immune resistant lung tumors as well as 2.72-folds higher CD3+ T cells in tumor tissues compared to that in the anti-4-1BB antibody treatment group.

Age-specific influences of refractive error and illuminance on pupil diameter.

To assess the most influential factor for pupil diameter changes among age, illuminance, and refractive state and reestablish the optimal procedures for clinical applications based on refractive state and illuminance for different age groups. The study was an observational study (repeated measure study). Participants included 219 Korean adults aged 20 to 69 years. Pupil diameters were measured using a pupilometer under scotopic, mesopic-low, and mesopic-high lighting conditions. Factor interactions among age, illuminance, and refractive state were evaluated using mixed linear model and chi-square automated interaction detection. Illuminance mainly contributed to variations in pupil diameter of participants over 50 years, whereas the refractive state was the dominant controlling factor for the pupil variation in participants below 50 years. For more generalized application, the pupil diameter decreased with older age and brighter illuminance (P < .001, inverse correlation, all comparisons). The mean pupil diameter was significantly higher in myopes and emmetropes than in hyperopes (P < .001). Pupil diameter variation modeled using the mixed model confirmed age, illuminance, and refractive error as significant factors (P < .001). Accounting for the interactions among age, illuminance, and refractive error and establishing their hierarchical dominance can be generalized using the chi-square automated interaction detection method and mixed model. Promoting age-dependent consideration for both illuminance and refractive state is necessary when pupil diameters play significant roles in clinical and manufacturing circumstances.

Akt1 Decreases Gcn5 Protein Stability through Regulating The Ubiquitin-Proteasome Pathway in Mouse Embryonic Fibroblasts.

General control non-derepressible 5 (Gcn5) is a member of histone acetyltransferase (HAT) that plays key roles during embryogenesis as well as in the development of various human cancers. Gcn5, an epigenetic regulator of Hoxc11, has been reported to be negatively regulated by Akt1 in the mouse embryonic fibroblasts (MEFs). However, the exact mechanism by which Akt1 regulates Gcn5 is not well understood. Using protein stability chase assay, we observed that Gcn5 is negatively regulated by Akt1 at the post-translational level in MEFs. The stability of Gcn5 protein is determined by the competitive binding with the protein partner that interacts with Gcn5. The interaction of Gcn5 and Cul4a-Ddb1 complex predominates and promotes ubiquitination of Gcn5 in the wild-type MEFs. On the other hand, in the Akt1-null MEFs, the interaction of Gcn5 and And-1 inhibits binding of Gcn5 and Cul4a-Dbd1 E3 ubiquitin ligase complex, thereby increasing the stability of the Gcn5 protein. Taken together, our study indicates that Akt1 negatively controls Gcn5 via the proteasomal degradation pathway, suggesting a potential mechanism that regulates the expression of Hox genes.

Pregnancy loss and Income in the Republic of Korea using National Health Insurance Service Data, 2008-2014.

BACKGROUND: Although unintentional pregnancy loss is common, national representative statistics are lacking in high-income East Asian countries undergoing rapid demographic changes. It is necessary to confirm the income inequality of pregnancy loss even in universal national health insurance. METHOD: Using National Health Insurance Service data between 2008 and 2014, the annual prevalence of pregnancy loss was enumerated, and differences in pregnancy loss according to age and income levels were assessed by multivariable Poisson regression. Joint-point regression was used to examine the trend of pregnancy loss. RESULT: On average, there was a 15.0% annual pregnancy loss among 3,941,020 pregnancy cases from 2008 to 2014. Pregnancy loss inequality increased stepwise with income levels except for the highest income group. After adjusting for income levels, the annual percent change of age-standardized prevalence significantly increased by 2.6% every year since 2011. CONCLUSION: Even in high-income countries with universal national health insurance, income inequality in pregnancy loss is observed. Further appraisal is needed to explain the increasing trend of pregnancy loss between 2011 and 2014 even after adjusting income.

Contracting Out National Immunization Program Does Not Improve Vaccination Rate Nor Socioeconomic Inequality: A Case Study of Seasonal Influenza Vaccination in South Korea.

The objective of the present study was to investigate if the policy for contracting out the Korean influenza National Immunization Program (NIP) for individuals aged ≥ 65 years affects a reduction in vaccination inequality based on gender and socioeconomic position (SEP). In South Korea, initially only public health centers provided influenza vaccination for free; however, starting from the fall of 2015, the program was expanded to include private medical institutions. The policy was expected to improve overall vaccination rate and reduce its inequality, through improving access to vaccination. The present study analyzed how the gap in the vaccination rate changed between before and after contracting out. A multivariate logistic regression model stratified by gender and SEP of individuals aged ≥ 65 years was used. The study also analyzed changes in the unvaccinated rates between before and after contracting out based on an interrupted time series model. The gap in the unvaccinated rate based on SEP present prior to contracting out of the NIP for individuals aged ≥ 65 years did not decrease afterwards. In particular, the step changes were 0.94% (95% confidence interval [CI]: 0.00, 1.89) and 1.34% (95% CI: 1.17, 1.52) in men and women, respectively. In the pre-policy period, among women, the unvaccinated rate of the medical aid beneficiaries group was 1.22-fold higher (95% CI: 1.12, 1.32) than that of the health insurance beneficiaries, and the difference was not reduced post-policy implementation (odds ratio: 1.27, 95% CI: 1.20, 1.36). The findings of the study were that contracting out of the NIP was not effective in improving vaccination rate nor resolving vaccination inequality. Future studies should focus on identifying the mechanism of vaccination inequality and exploring measures for resolving such inequality.

Mitofusin-2 Promotes the Epithelial-Mesenchymal Transition-Induced Cervical Cancer Progression.

High expression of mitofusin-2 (MFN2), a mitochondrial fusion protein, has been frequently associated with poor prognosis of patients with cervical cancer. Here, we aimed to identify the function of MFN2 in cervical cancer to understand its influence on disease prognosis. To this end, from cervical adenocarcinoma, we performed an MTT assay and quantitative RT-PCR (qRT-PCR) analysis to assess the effects of MFN2 on the proliferation and of HeLa cells. Then, colony-formation ability and tumorigenesis were evaluated using a tumor xenograft mouse model. The migration ability related to MFN2 was also measured using a wound healing assay. Consequently, epithelial-mesenchymal transition (EMT) of MFN2-knockdowned HeLa cells originating from adenocarcinoma. markers related to MFN2 were assessed by qRT-PCR. Clinical data were analyzed using cBioPortal and The Cancer Genome Atlas. We found that MFN2 knockdown reduced the proliferation, colony formation ability, migration, and in vivo tumorigenesis of HeLa cells. Primarily, migration of MFN2-knockdowned HeLa cells decreased through the suppression of EMT. Thus, we concluded that MFN2 facilitates cancer progression and in vivo tumorigenesis in HeLa cells. These findings suggest that MFN2 could be a novel target to regulate the EMT program and tumorigenic potential in HeLa cells and might serve as a therapeutic target for cervical cancer. Taken together, this study is expected to contribute to the treatment of patients with cervical cancer.

NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer.

Endocrine therapy is used to treat estrogen receptor (ER)-positive breast cancer. Tamoxifen is effective against this cancer subtype. Nonetheless, approximately 30% of patients treated with tamoxifen acquire resistance, resulting in therapeutic challenges. NR4A1 plays key roles in processes associated with carcinogenesis, apoptosis, DNA repair, proliferation, and inflammation. However, the role of NR4A1 in tamoxifen-resistant ER-positive breast cancer has not yet been elucidated. Here, we propose that NR4A1 is a promising target to overcome tamoxifen resistance. NR4A1 gene expression was downregulated in tamoxifen-resistant MCF7 (TamR) cells compared to that in MCF7 cells. Kaplan-Meier plots were used to identify high NR4A1 expression correlated with increased survival rates in patients with ER-positive breast cancer following tamoxifen treatment. Gain and loss of function experiments showed that NR4A1 restores sensitivity to tamoxifen by regulating cell proliferation, migration, invasion, and apoptosis. NR4A1 localized to the cytoplasm enhanced the expression of apoptotic factors. In silico and in vitro analyses revealed that NR4A1 enhanced responsiveness to tamoxifen by suppressing ERK signaling in ER-positive breast cancer, suggesting that the NR4A1/ERK signaling axis modulates tamoxifen resistance. These results indicate that NR4A1 could be a potential therapeutic target to overcome tamoxifen resistance in ER-positive breast cancer.

HOXB5 Confers Tamoxifen Resistance in Breast Cancer Cells and Promotes Tumor Aggression and Progression.

BACKGROUND/AIM: ER-positive breast cancer patients commonly undergo endocrine therapy with drugs such as tamoxifen. Despite tamoxifen being a highly effective drug, long-term treatment results in resistance in one-third of the patients. Although many explanations for the development of tamoxifen resistance have been put forward, a clearly defined underlying mechanism is still lacking. MATERIALS AND METHODS: The expression level of HOXB5 was evaluated between MCF7 breast cancer cells and tamoxifen-resistant MCF7 (TAMR) cells by RT-PCR. Then, the effect of HOXB5 on invasion and migration abilities as well as on cancer stemness were investigated through 3D culture and spheroid formation assay. RESULTS: In this study, we provide evidence that HOXB5 is up-regulated in TAMR cells. EGFR is concurrently overexpressed, and the EGFR signaling cascade is activated, resulting in migratory and invasive phenotypes in TAMR cells compared to MCF7 cells. However, HOXB5 knockdown in TAMR cells resulted in the de-activation of the EGFR signaling pathway, less aggressive phenotypes and restoration of sensitivity to tamoxifen treatment. More interestingly, TAMR cells expressed higher levels of stem cell markers, and as a result, their enhanced stemness allowed for a better formation of spheroids than MCF7 cells. When HOXB5 was overexpressed in MCF7 cells, they were able to form a larger number of spheroids as in TAMR cells. CONCLUSION: HOXB5 is one of the key factors involved in tumor aggression and progression in tamoxifen-resistant breast cancer cells.

HOXA5 confers tamoxifen resistance via the PI3K/AKT signaling pathway in ER-positive breast cancer.

Tamoxifen is a commonly used drug to treat estrogen receptor-positive patients with breast cancer. Despite the outstanding efficacy of tamoxifen, approximately one-third of patients develop resistance toward it, thereby presenting a therapeutic challenge. HOX genes may be involved in the acquisition of tamoxifen resistance. In this study, we identified HOXA5, a member of the HOX gene family, as a marker of tamoxifen resistance. Using ChIP assay, we found that HOXA5 expression was significantly overexpressed in tamoxifen-resistant MCF7 (TAMR) breast cancer cells because of reduced H3K27me3 binding. HOXA5 upregulation resulted in activation of the PI3K/AKT signaling cascade, which in turn, led to p53 and p21 reduction, ultimately making the TAMR cells less apoptotic. Furthermore, elevated HOXA5 expression resulted in breast cancer cells acquiring more mesenchymal-like and stem cell traits associated with aggressive breast cancer phenotypes. In conclusion, our results delineate a mechanism by which HOXA5 promotes tumorigenesis, cancer progression, and tamoxifen resistance in breast cancer cells.