The long noncoding RNA HOTAIR plays significant roles in promoting cancer metastasis. However, how it conveys an invasive advantage in cancer cells is not clear. Here we identify the chondroitin ...sulfotransferase CHST15 (GalNAc4S‐6ST) as a novel HOX transcript antisense intergenic RNA (HOTAIR) target gene using RNA profiling and show that CHST15 is required for HOTAIR‐mediated invasiveness in breast cancer cells. CHST15 catalyzes sulfation of the C6 hydroxyl group of the N‐acetyl galactosamine 4‐sulfate moiety in chondroitin sulfate to form the 4,6‐disulfated chondroitin sulfate variant known as the CS‐E isoform. We show that HOTAIR is necessary and sufficient for CHST15 transcript expression. Inhibition of CHST15 by RNA interference abolished cell invasion promoted by HOTAIR but not on HOTAIR‐mediated migratory activity. Conversely, reconstitution of CHST15 expression rescued the invasive activity of HOTAIR‐depleted cells. In corroboration with this mechanism, blocking cell surface chondroitin sulfate using a pan‐CS antibody or an antibody specifically recognizes the CS‐E isoform significantly suppressed HOTAIR‐induced invasion. Inhibition of CHST15 compromised tumorigenesis and metastasis in orthotopic breast cancer xenograft models. Furthermore, the expression of HOTAIR closely correlated with the level of CHST15 protein in primary as well as metastatic tumor lesions. Our results demonstrate a novel mechanism underlying the function of HOTAIR in tumor progression through programming the context of cell surface glycosaminoglycans. Our results further establish that the invasive and migratory activities downstream of HOTAIR are distinctly regulated, whereby CHST15 preferentially controls the arm of invasiveness. Thus, the HOTAIR‐CHST15 axis may provide a new avenue toward novel therapeutic strategies and prognosis biomarkers for advanced breast cancer.
What's new?
The long noncoding RNA HOTAIR is known to influence cancer growth, and now researchers have identified a molecule that mediates the effect. Using both loss‐of‐function and gain‐of‐function experiments, these authors identified chondroitin sulfotransferase (CHST15) as a downstream target of HOTAIR required for invasive activity of breast cancer cells. Antibodies against cell surface chondroitin sulfate suppressed HOTAIR‐induced invasion in xenograft models. Further, HOTAIR expression correlates with CHST15 protein both in primary tumors and metastases. The identification of HOTAIR‐CHST15 regulation of cell surface moieties could lead to new therapeutic targets or diagnostic biomarkers for breast cancer.
Abstract
Aromatase inhibitors (AIs) are standard adjuvant therapy for postmenopausal women with oestrogen receptor-positive, early-stage, and metastatic breast cancer. Although effective, the risk of ...falls due to AI-associated knee joint pain significantly increased. The aim of this study was to evaluate the therapeutic effects of yoga and massage on AI-associated knee joint pain. Breast cancer survivors were randomly assigned to a 6-week yoga intervention-2-week rest-6-week massage exposure (Yoga first, n = 30) or a 6-week massage intervention-2-week rest-6-week yoga exposure (Massage first, n = 30). Evaluations of the treatment efficacy were made at baseline, post-intervention, and post-exposure using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale, plasma cytokine levels, and changes in meridian energy. The results showed that yoga, superior to massage intervention, significantly reduced AI-associated knee joint pain, as demonstrated by the WOMAC pain score. The yoga intervention improvements were also associated with changes in plasma cytokine levels and meridian energy changes. In conclusion, this study provides scientific evidence that yoga was more effective than massage for reducing AI-associated knee joint pain. Meridian energy changes may provide another scientific, objective, non-invasive way to monitor the therapeutic effects of yoga and investigate another alternative, complementary medicine.
Development of acquired resistance to lapatinib, a dual epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor, severely limits the duration ...of clinical response in advanced HER2‐driven breast cancer patients. Although the compensatory activation of the PI3K/Akt survival signal has been proposed to cause acquired lapatinib resistance, comprehensive molecular mechanisms remain required to develop more efficient strategies to circumvent this therapeutic difficulty. In this study, we found that suppression of HER2 by lapatinib still led to Akt inactivation and elevation of FOX3a protein levels, but failed to induce the expression of their downstream pro‐apoptotic effector p27kip1, a cyclin‐dependent kinase inhibitor. Elevation of miR‐221 was found to contribute to the development of acquired lapatinib resistance by targeting p27kip1 expression. Furthermore, upregulation of miR‐221 was mediated by the lapatinib‐induced Src family tyrosine kinase and subsequent NF‐κB activation. The reversal of miR‐221 upregulation and p27kip1 downregulation by a Src inhibitor, dasatinib, can overcome lapatinib resistance. Our study not only identified miRNA‐221 as a pivotal factor conferring the acquired resistance of HER2‐positive breast cancer cells to lapatinib through negatively regulating p27kip1 expression, but also suggested Src inhibition as a potential strategy to overcome lapatinib resistance.
The downregulation of p27kip1 by Src/NF‐κB axis‐induced miR‐221 expression as a novel mechanistic insight into lapatinib resistance. Targeting Src would be a promising strategy to overcome lapatinib resistance.
Sarcopenia, a newly recognized geriatric syndrome, is characterized by age-related decline of skeletal muscle plus low muscle strength and/or physical performance. Previous studies have confirmed the ...association of sarcopenia and adverse health outcomes, such as falls, disability, hospital admission, long term care placement, poorer quality of life, and mortality, which denotes the importance of sarcopenia in the health care for older people. Despite the clinical significance of sarcopenia, the operational definition of sarcopenia and standardized intervention programs are still lacking. It is generally agreed by the different working groups for sarcopenia in the world that sarcopenia should be defined through a combined approach of muscle mass and muscle quality, however, selecting appropriate diagnostic cutoff values for all the measurements in Asian populations is challenging. Asia is a rapidly aging region with a huge population, so the impact of sarcopenia to this region is estimated to be huge as well. Asian Working Group for Sarcopenia (AWGS) aimed to promote sarcopenia research in Asia, and we collected the best available evidences of sarcopenia researches from Asian countries to establish the consensus for sarcopenia diagnosis. AWGS has agreed with the previous reports that sarcopenia should be described as low muscle mass plus low muscle strength and/or low physical performance, and we also recommend outcome indicators for further researches, as well as the conditions that sarcopenia should be assessed. In addition to sarcopenia screening for community-dwelling older people, AWGS recommends sarcopenia assessment in certain clinical conditions and healthcare settings to facilitate implementing sarcopenia in clinical practice. Moreover, we also recommend cutoff values for muscle mass measurements (7.0 kg/m(2) for men and 5.4 kg/m(2) for women by using dual X-ray absorptiometry, and 7.0 kg/m(2) for men and 5.7 kg/m(2) for women by using bioimpedance analysis), handgrip strength (<26 kg for men and <18 kg for women), and usual gait speed (<0.8 m/s). However, a number of challenges remained to be solved in the future. Asia is made up of a great number of ethnicities. The majority of currently available studies have been published from eastern Asia, therefore, more studies of sarcopenia in south, southeastern, and western Asia should be promoted. On the other hand, most Asian studies have been conducted in a cross-sectional design and few longitudinal studies have not necessarily collected the commonly used outcome indicators as other reports from Western countries. Nevertheless, the AWGS consensus report is believed to promote more Asian sarcopenia research, and most important of all, to focus on sarcopenia intervention studies and the implementation of sarcopenia in clinical practice to improve health care outcomes of older people in the communities and the healthcare settings in Asia.
Background
Treatment for stage III non‐small cell lung cancer (NSCLC) of unresectable disease mainly involves concurrent chemoradiation (CRT). Post‐CRT consolidation treatment with durvalumab is a ...major therapeutic advance that provides survival benefit in this group of patients. However, the performance of this treatment strategy remains to be studied in a real‐world setting.
Methods
A total of 31 patients who had disease control post‐CRT were included in the durvalumab early access program (EAP) as an intent‐to‐treat cohort and retrospectively reviewed for post‐CRT progression‐free survival (PFS) and time to metastatic disease or death (TMDD). The neutrophil‐to‐lymphocyte ratio (NLR) at the initiation of durvalumab was analyzed in 29 patients.
Results
The median time from the completion of concurrent CRT to the initiation of durvalumb was 2.8 months. The objective response was 25.8% and the 12 month PFS and TMDD‐free rate were 56.4% and 66.9%, respectively. The low NLR patients showed a significantly longer post‐CRT PFS (not reach vs. 12.0 months 95% CI: 5.5–not estimable; P = 0.040; the hazard ratio for disease progression or death, 0.23 95% CI: 0.05–1.00; P = 0.048) and the 12 month post‐CRT PFS rate (82.5 vs. 42.6%). The post‐CRT TMDD (not reach vs. 12.6 months, 95% CI: 10.8–not estimable; P = 0.010; the hazard ratio for distant metastasis or death, 0.11 95% CI: 0.01–0.88; P = 0.037) and 12 month post‐CRT TMDD‐free rate (90.9 vs. 57.1%) were also significantly higher in the low NLR patients.
Conclusions
Durvalumab consolidation treatment in real‐world patients showed substantial efficacy and the correlation with the NLR level warrants further investigation.
Lung adenocarcinoma (ADC) is the predominant histological type of lung cancer, and radiotherapy is one of the current therapeutic strategies for lung cancer treatment. Unfortunately, biological ...complexity and cancer heterogeneity contribute to radioresistance development. Karyopherin α2 (KPNA2) is a member of the importin α family that mediates the nucleocytoplasmic transport of cargo proteins. KPNA2 overexpression is observed across cancer tissues of diverse origins. However, the role of KPNA2 in lung cancer radioresistance is unclear. Herein, we demonstrated that high expression of KPNA2 is positively correlated with radioresistance and cancer stem cell (CSC) properties in lung ADC cells. Radioresistant cells exhibited nuclear accumulation of KPNA2 and its cargos (OCT4 and c‐MYC). Additionally, KPNA2 knockdown regulated CSC‐related gene expression in radioresistant cells. Next‐generation sequencing and bioinformatic analysis revealed that STAT1 activation and nuclear phospholipid scramblase 1 (PLSCR1) are involved in KPNA2‐mediated radioresistance. Endogenous PLSCR1 interacting with KPNA2 and PLSCR1 knockdown suppressed the radioresistance induced by KPNA2 expression. Both STAT1 and PLSCR1 were found to be positively correlated with dysregulated KPNA2 in radioresistant cells and ADC tissues. We further demonstrated a potential positive feedback loop between PLSCR1 and STAT1 in radioresistant cells, and this PLSCR1‐STAT1 loop modulates CSC characteristics. In addition, AKT1 knockdown attenuated the nuclear accumulation of KPNA2 in radioresistant lung cancer cells. Our results collectively support a mechanistic understanding of a novel role for KPNA2 in promoting radioresistance in lung ADC cells.
Nuclear KPNA2 promotes radioresistance and regulates cancer stem cell properties in lung adenocarcinoma cells. A loop between PLSCR1 and STAT1 is involved in KPNA2‐mediated radioresistance.
ZFP36 family members include ZFP36, ZFP36L1, and ZFP36L2, which belong to CCCH-type zinc finger proteins with two tandem zinc finger (TZF) regions. Whether ZFP36L1 and ZFP36L2 have antiproliferative ...activities similar to that of ZFP36 is unclear. In this study, when ZFP36L1 or ZFP36L2 was overexpressed in T-REx-293 cells, cell proliferation was dramatically inhibited and the cell cycle was arrested at the G1 phase. The levels of cell-cycle-related proteins, including cyclin B, cyclin D, cyclin A, and p21, decreased; however, p53 increased in ZFP36L1-or ZFP36L2-overexpressing T-REx-293 cells. Forced expression of ZFP36L1 or ZFP36L2 also inhibited cell proliferation and cyclin D gene expression in three human colorectal cancer cell lines: HCT116 p53
, HCT116 p53
, and SW620 (mutated p53) cells. However, it increased p53 and p21 expression only in HCT116 p53
cells. Knockdown of ZFP36L1 or ZFP36L2 increased cell proliferation and cyclin D expression; furthermore, the mutation of the TZF of ZFP36L1 or ZFP36L2 caused them to lose their antiproliferative ability, to the extent that they could not inhibit cyclin D expression in these three cell lines. The results indicated that ZFP36L1 and ZFP36L2 play a negative role in cell proliferation; the underlying mechanisms might be mediated through a cyclin D-dependent and p53-independent pathway.
We investigate the role of external social networks in corporate tax strategies. Using data on Taiwan-listed nonfinancial firms from 2004 to 2022, we construct executives’ external social networks by ...measuring their ties with the directors or executives of other listed firms with the similar characteristics of educational backgrounds and working experiences as well as other activities such as training courses, business forums, and meetings. Our empirical analyses show that firms whose CEOs and CFOs have stronger network ties are more likely to aggressively avoid taxes, and such a phenomenon is robust to different regression models. With more insightful depth, the network-tax relations are significant only for subsamples of firms whose executives have a financial or accounting background. We contribute to the literature on tax avoidance by demonstrating how an external social network is another crucial characteristic of executives that influences corporate tax avoidance.
ABSTRACT
Manuscript Type: Empirical
Research Question/Issue: Using the data of the 20 largest financial institutions from G8 countries, we explore whether the performance is higher for financial ...institutions with more independent directors on different committees during the 2007–08 financial crisis. We also examine the moderating effect of a country‐level civil law dummy and firm‐level excessive risk‐taking behaviors on the independence‐performance relationships.
Research Findings/Insights: The empirical evidence shows that the performance during the crisis period is higher for financial institutions with more independent directors on auditing and risk committees. The influence of committee independence on the performance is particularly stronger for civil law countries. In addition, the independence‐performance relationships are more significant in financial institutions with excessive risk‐taking behaviors.
Theoretical/Academic Implications: Our findings complement existing works to partially resolve the independence‐performance relationship controversies by exploring the independence of different committees. The moderating effects of civil law countries and excessive risk‐taking firms further address the governance environment's role in the effectiveness of director independence.
Practitioner/Policy Implications: Our results provide important policy implications for financial institutions. The regulation authorities should enhance regulation compliance to improve director independence, particularly for auditing and risk committees in banking industry. Independent directors in the banking industry are supposed to put more emphasis on excessive risk‐taking behaviors, as the financial institutions profit from risk‐bearing earnings.
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