Mechanism underlying thyroid cancer progression and treatment resistance remains an unsolved problem in clinical practice. Endoplasmic reticulum (ER) proteins modulate cell biosynthesis and mediate tumor progression, among which Reticulon 3 (RTN3) is verified to play important roles in cancers. However, its effect in thyroid cancer has not been clarified. Meanwhile, cholesterol is found to contribute to proliferation and drug resistance in many tumors. As ER is the primary site of cholesterol synthesis, we aimed to study how RTN3 regulates cholesterol concentration and influences tumor progression and sensitivity to MEK inhibitors in thyroid cancer. This study found that RTN3 is low-expressed in thyroid cancer, and is related to poor prognosis and insensitivity to MEK inhibitors. It binds to a cholesterol synthesis enzyme DHCR7 and promotes its ubiquitination. Downregulation of RTN3 lead to stabilization of DHCR7 and elevate cholesterol concentration, activating EGFR/ERK pathway and contributes to progression of thyroid cancer, which can be rescued by HMG-CoA reductase inhibitor Simvastatin. We identified RTN3 as a tumor suppressor and a biomarker of sensitivity to MEK inhibitors and verified the role of cholesterol in drug resistance. The combination of statins provides a novel therapeutic method in patients resistant to MEK inhibitors.

Thyroid cancer is the most common endocrine cancer with a steadily rising incidence. In recent years, artificial intelligence, particularly deep learning, has shown great potential in assisting with the diagnosis of thyroid nodules. Despite these advances, existing approaches still face several challenges, including limited single-modal information, inadequate multimodal feature fusion, and a scarcity of multimodal datasets. Hence, this study proposes a Two-stage Text-driven Multimodal Network (TTM-Net), a novel network designed for thyroid nodule ultrasound diagnosis. In the first stage, a Text-Driven Vision Pretraining (TDVP) strategy is introduced to align visual and textual features using large-scale unlabeled text-image pairs, thereby enhancing the visual encoder's ability to capture clinically relevant patterns from the thyroid ultrasound images. In the second stage, supervised classification training is conducted using labeled data. Visual and textual features are integrated via the Cross-Modal Concat-Attention Fusion (CMCAF) module, and a joint optimization strategy is employed to improve diagnostic performance. To overcome the limitations of TI RADS, we propose a Thyroid Nodule Ultrasound Feature Classification System for Artificial Intelligence (TNUFCS-AI), which integrates clinical domain knowledge. Based on this system, we constructed a structured multimodal thyroid dataset comprising 22,544 ultrasound images and corresponding clinical reports from 9466 patients. Experiments show that TTM-Net outperforms SOTA methods in classification accuracy, stability, and interpretability, achieving (94.98 +/- 0.15%) accuracy. In summary, TTM-Net significantly improves the diagnostic performance and increases the model robustness while alleviating the dependence on labeled data, providing a viable solution for developing high-performance, interpretable, and deployable AI-assisted diagnostic systems for thyroid nodules.

Background The incidence of papillary thyroid cancer (PTC) has risen sharply over the past several decades. Early identification of high-risk PTC is crucial to mitigate the societal burden associated with its overdiagnosis. ER-phagy, a selective form of autophagy targeting the endoplasmic reticulum, is categorized into macro-ER-phagy and micro-ER-phagy. To date, the role of ER-phagy receptors and their impact on risk stratification and progression in thyroid cancer remain unclear. Methods This study employed an integrative approach combining bioinformatics analysis with wet-lab molecular biology experiments. Transcriptomic and clinical data from TCGA were processed using Xiantaoxueshu, GSCA, TIMER, and TISIDB platforms to assess differential expression, survival, ROC characteristics, and KEGG/GO enrichment, as well as immune infiltration. In vitro, shRNAs targeting RTN3, SEC62, or ATL3 were transfected into TPC-1 and CAL-62 cells to silence gene expression, validated by RT-qPCR and Western Blot. Cell proliferation, migration, and invasion were assessed by CCK-8, EdU, colony formation, wound healing, and Transwell assays. All experiments were performed in at least three independent replicates, and the resulting data were subjected to statistical analysis. Data were analyzed using SPSS 18.0 and GraphPad Prism 9.3.0. Quantitative results are presented as mean ± SEM. Independent-samples t-tests, univariate/multivariate Cox regression and LASSO Cox regression were used; P < 0.05 was considered significant. Results Comprehensive analysis of all ER-phagy receptors using public databases revealed that several receptors significantly impact the diagnosis and prognosis of thyroid cancer. We also characterized the mutation and methylation pattern of these receptors. Furthermore, these genes were also closely associated with immune infiltration in thyroid cancer. Of note, RTN3, SEC62 and ATL3 appeared to have distinct importance in thyroid cancer. All three genes were downregulated and their reduced expression was significantly related to poor survival in thyroid cancer. Receiver Operating Characteristic (ROC) curve analysis demonstrated that these markers hold substantial promise for thyroid cancer diagnosis, particularly RTN3 and SEC62. Immune-related analysis indicated a strong correlation with immune infiltration, implying a potential role in modulating the immune landscape of thyroid cancer. Functional assays demonstrated that knockdown of RTN3, SEC62, and ATL3 promoted proliferation and metastasis of thyroid cancer cells in vitro. Western blot analysis indicated that this process is likely mediated by the Epithelial-Mesenchymal Transition (EMT). Conclusion In summary, our findings indicate that ER-phagy represents a promising avenue for thyroid cancer diagnosis. Specifically, RTN3, SEC62, and ATL3 were found to suppress the proliferation and metastasis of thyroid cancer cells, underscoring their pivotal roles in disease progression.

Follicular-cell-derived thyroid carcinoma, while typically associated with a favorable prognosis, can undergo dedifferentiation into poorly differentiated (PDTC) or anaplastic thyroid carcinoma (ATC), leading to enhanced aggressiveness and radioiodine resistance. This review systematically examines the genetic and molecular mechanisms driving this pathological progression, highlighting the roles of key mutations-such as BRAF, RAS, TERT, and TP53-and the disregulation of signaling pathways, including MAPK and PI3K/AKT. These alterations promote the loss of thyroid-specific functions, including iodide metabolism, and correlate with poor clinical outcomes. In recent years, therapeutic strategies aimed at tumor redifferentiation have emerged as a promising approach for radioiodine-refractory disease. We summarize recent advances in the use of targeted agents, particularly BRAF and MEK inhibitors, to restore radioiodine avidity and improve treatment response. While early clinical studies show encouraging results, including tumor shrinkage and restored RAI uptake in selected patients, challenges such as treatment resistance and patient selection remain. Future efforts should focus on refining molecular stratification, developing rational combination therapies, and integrating novel modalities such as immunotherapy to overcome resistance. A deeper understanding of redifferentiation mechanisms not only provides insights into thyroid cancer progression but also supports the development of personalized treatment strategies for high-risk patients.

Background Triple-negative breast cancer is a complex breast malignancy subtype characterized by poor prognosis. The pursuit of effective therapeutic approaches for this subtype is considerably challenging. Notably, recent research has illuminated the key role of the tricarboxylic acid cycle in cancer metabolism and the complex landscape of tumor development. Concurrently, an emerging body of evidence underscores the noteworthy role that long non-coding RNAs play in the trajectory of breast cancer development. Despite this growing recognition, the exploration of whether long non-coding RNAs can influence breast cancer progression by modulating the tricarboxylic acid cycle has been limited. Moreover, the underlying mechanisms orchestrating these interactions have not been identified. Methods The expression levels of LINC00571 and IDH2 were determined through the analysis of the public TCGA dataset, transcriptome sequencing, qRT‒PCR, and Western blotting. The distribution of LINC00571 was assessed using RNA fluorescence in situ hybridization. Alterations in biological effects were evaluated using CCK-8, colony formation, EdU, cell cycle, and apoptosis assays and a tumor xenograft model. To elucidate the interaction between LINC00571, HNRNPK, and ILF2, RNA pull-down, mass spectrometry, coimmunoprecipitation, and RNA immunoprecipitation assays were performed. The impacts of LINC00571 and IDH2 on tricarboxylic acid cycle metabolites were investigated through measurements of the oxygen consumption rate and metabolite levels. Results This study revealed the complex interactions between a novel long non-coding RNA (LINC00571) and tricarboxylic acid cycle metabolism. We validated the tumor-promoting role of LINC00571. Mechanistically, LINC00571 facilitated the interaction between HNRNPK and ILF2, leading to reduced ubiquitination and degradation of ILF2, thereby stabilizing its expression. Furthermore, ILF2 acted as a transcription factor to enhance the expression of its downstream target gene IDH2. Conclusions Our study revealed that the LINC00571/HNRNPK/ILF2/IDH2 axis promoted the progression of triple-negative breast cancer by regulating tricarboxylic acid cycle metabolites. This discovery provides a novel theoretical foundation and new potential targets for the clinical treatment of triple-negative breast cancer.

Tamoxifen (TAM) is the frontline therapy for estrogen receptor-positive (ER+) breast cancer in premenopausal women that interrupts ER signaling. As tumors with elevated heterogeneity, amounts of ER-negative (ER−) cells are present in ER+ breast cancer that cannot be directly killed by TAM. Despite complete remissions have been achieved in clinical practice, the mechanism underlying the elimination of ER− cells during TAM treatment remains an open issue. Herein, we deciphered the elimination of ER− cells in TAM treatment from the perspective of the bystander effect. Markable reductions were observed in tumorigenesis of ER− breast cancer cells by applying both supernatants from TAM-treated ER+ cells and a transwell co-culture system, validating the presence of a TAM-induced bystander effect. The major antitumor protein derived from ER+ cells, peptidyl-prolyl cis-trans isomerase B (PPIB), is the mediator of the TAM-induced bystander effect identified by quantitative proteomics. The attenuation of ER− cells was attributed to activated BiP/eIF2α/CHOP axis and promoted endoplasmic reticulum stress (ERS)-induced apoptosis, which can also be triggered by PPIB independently. Altogether, our study revealed a novel TAM-induced bystander effect in TAM treatment of ER+ breast cancer, raising the possibility of developing PPIB as a synergistic antitumor agent or even substitute endocrine therapy.

Breast cancer has become the most commonly diagnosed cancer. Heterogeneous nuclear ribonucleoprotein C (HNRNPC), a reader of N6-methyladenosine (m6A), has been observed to be upregulated in various types of cancer. Nevertheless, the role of HNRNPC in breast cancer and whether it is regulated by m6A modification deserve further investigation. The expression of HNRNPC in breast cancer was examined by quantitative real-time polymerase chain reaction and western blot analysis. RNA immunoprecipitation was performed to validate the binding relationships between HNRNPC and WD repeat domain 77 (WDR77). The effects of HNRNPC and m6A regulators on WDR77 were investigated by actinomycin D assay. The experiments in vivo were conducted in xenograft models. In this research, we found that HNRNPC was highly expressed in breast cancer, and played a crucial role in cell growth, especially in the luminal subtype. HNRNPC could combine and stabilize WDR77 mRNA. WDR77 successively drove the G1/S phase transition in the cell cycle and promoted cell proliferation. Notably, this regulation axis was closely tied to the m6A modification status of WDR77 mRNA. Overall, a critical regulatory mechanism was identified, as well as promising targets for potential treatment strategies for luminal breast cancer.

PurposeThe incidence of thyroid cancer is growing fast and surgery is the most significant treatment of it. For patients with unilateral cN0 papillary thyroid cancer whether to dissect contralateral central lymph node is still under debating. Here, we aim to provide a machine learning based prediction model of contralateral central lymph node metastasis using demographic and clinical data.Methods2225 patients with unilateral cN0 papillary thyroid cancer from Wuhan Union Hospital were retrospectively studied. Clinical and pathological features were compared between patients with contralateral central lymph node metastasis and without. Six machine learning models were constructed based on these patients and compared using accuracy, sensitivity, specificity, area under the receiver operating characteristic and decision curve analysis. The selected models were then verified using data from Differentiated Thyroid Cancer in China study. All statistical analysis and model construction were performed by R software.ResultsMale, maximum diameter larger than 1cm, multifocality, ipsilateral central lymph node metastasis and younger than 50 years were independent risk factors of contralateral central lymph node metastasis. Random forest model performed better than others, and were verified in external validation cohort. A web calculator was constructed.ConclusionsGender, maximum diameter, multifocality, ipsilateral central lymph node metastasis and age should be considered for contralateral central lymph node dissection. The web calculator based on random forest model may be helpful in clinical decision.

IntroductionCancer is a crucial public health problem and one of the leading causes of death worldwide. Previous studies have suggested that GPX3 may be involved in cancer metastasis and chemotherapy resistance. However, how GPX3 affects cancer patients' outcomes and the underlying mechanism remains unclear. MethodsSequencing data and clinical data from TCGA, GTEx, HPA, and CPTAC were used to explore the relationship between GPX3 expression and clinical features. Immunoinfiltration scores were used to assess the relationship between GPX3 and the tumor immune microenvironment. Functional enrichment analysis was used to predict the role of GPX3 in tumors. Gene mutation frequency, methylation level, and histone modification were used to predict the GPX3 expression regulation method. Breast, ovarian, colon, and gastric cancer cells were used to investigate the relationship between GPX3 expression and cancer cell metastasis, proliferation, and chemotherapy sensitivity. ResultsGPX3 is down-regulated in various tumor tissues, and GPX3 expression level can be used as a marker for cancer diagnosis. However, GPX3 expression is associated with higher stage and lymph node metastasis, as well as poorer prognosis. GPX3 is closely related to thyroid function and antioxidant function, and its expression may be regulated by epigenetic inheritance such as methylation modification or histone modification. In vitro experiments, GPX3 expression is associated with cancer cell sensitivity to oxidant and platinum-based chemotherapy and is involved in tumor metastasis in oxidative environments. DiscussionWe explored the relationship between GPX3 and clinical features, immune infiltration characteristics, migration and metastasis, and chemotherapy sensitivities of human cancers. We further investigated the potential genetic and epigenetic regulation of GPX3 in cancer. Our results suggested that GPX3 plays a complicated role in the tumor microenvironment, simultaneously promoting metastasis and chemotherapy resistance in human cancers.

Background Extrathyroidal extension is a major risk factor for poor prognosis in papillary thyroid cancer. However, the effect of different degrees of extrathyroidal extension on prognosis remains controversial. We performed a retrospective study to elucidate how the extent of extrathyroidal extension in papillary thyroid cancer affected the clinical prognosis of patients and its covariates. Methods The study included 108,426 patients with papillary thyroid cancer. We categorized the extent of extension into none, capsule, strap muscles, and other organs. Three causal inference methods for retrospective studies, namely, inverse probability of treatment weighting, standardized mortality ratio weighting, and propensity score matching analysis, were used to minimize potential selection bias. Kaplan–Meier analysis and univariate Cox regression analyses were applied to analyze the precise effect of ETE on survival in papillary thyroid cancer patients. Results In the Kaplan–Meier survival analysis, only extrathyroidal extension into or beyond the strap muscles was statistically significant for both overall survival (OS) and thyroid cancer-specific survival (TCSS). In univariate Cox regression analyses before and after matching or weighting based on causal inference, extrathyroidal extension into soft tissues or other organs is a high-risk factor for both overall survival and thyroid cancer-specific survival. Sensitivity analysis revealed that lower overall survival was observed in patients with older age (≥55) and larger tumor size (>2 cm) of papillary thyroid cancer with extrathyroidal extension into or beyond the strap muscles. Conclusions Our study indicates that extrathyroidal extension into soft tissues or other organs is a high-risk factor in all papillary thyroid cancer. Even though invasion into the strap muscles did not seem to be a marker for poor prognosis, it still impaired the overall survival of patients with older age (≥55 years old) or larger tumor size (>2 cm). Further investigation is needed to confirm our results and to clarify further risk factors independent of extrathyroidal extension.

Breast cancer is the primary cause of cancer-related deaths in women. Tamoxifen (TAM) is the preferred drug for treating premenopausal luminal-type breast cancer, but TAM resistance restricts its ability to benefit patients. To date, the mechanism of this resistance remains unclear, and there is currently no effective treatment for reversing it. The expression of indoleamine 2,3-dioxygenase 1 (IDO1) has been shown to be elevated in various malignancies. Here, we aimed to investigate the role of IDO1 in TAM-resistant breast cancer. We confirmed that IDO1 is strongly expressed in TAM-resistant breast cancer, and it mediates drug-resistant cell proliferation, metastasis, and TAM resistance in vivo and in vitro through interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3). We also found that the mechanism by which TAM upregulates IDO1 is dependent on STAT1 activation. In summary, IDO1 regulates TAM resistance and can serve as a novel target for treatment of TAM-resistant breast cancer.

Papillary thyroid cancer (PTC) is one of the malignancies with an excellent prognosis. However, in PTC, progression or dedifferentiation into poorly differentiated thyroid cancer (PDTC) or anaplastic thyroid cancer (ATC) extremely jeopardizes patients' prognosis. MMP1 is a zinc-dependent endopeptidase, and its role in PTC progression and dedifferentiation is unclear. In this study, transcriptome data of PDTC/ATC and PTC from the Gene Expression Omnibus and The Cancer Genome Atlas databases were utilized to perform an integrated analysis of MMP1 as a potential regulator of tumor progression and dedifferentiation in PTC. Both bulk and single-cell RNA-sequencing data confirmed the high expression of MMP1 in ATC tissues and cells, and further study verified that MMP1 possessed good diagnostic and prognostic value in PTC and PDTC/ATC. Up-regulated MMP1 was found to be positively related to more aggressive clinical characteristics, worse survival, extracellular matrix-related pathways, oncogenic immune microenvironment, more mutations, higher stemness, and more dedifferentiation of PTC. Meanwhile, in vitro experiments verified the high level of MMP1 in PDTC/ATC cell lines, and MMP1 knockdown and its inhibitor triolein could both inhibit the cell viability of PTC and PDTC/ATC. In conclusion, our findings suggest that MMP1 is a potential regulator of tumor progression and dedifferentiation in PTC, and might become a novel therapeutic target for PTC, especially for more aggressive PDTC and ATC.

*These authors contributed equally to this work Purpose: Papillary thyroid cancer (PTC) patients could obtain poor prognosis if they have lymph node metastasis, identification of informative and robust biomarkers for predicting cervical lymph node metastasis is critical for improving clinical decision-making and patient prognosis. Materials and Methods: In this study, we analyzed the expression of X box binding protein 1 spliced-form (XBP1s) in 41 PTC tissue samples and extended our findings using public databases, then we investigated how XBP1s’ contributed to PTC progression in vitro. Results: We found that XBP1s’ expression was lower in PTC patients with cervical lymph node metastasis than non-metastasis patients by immunohistochemical analysis. With publicly accessible dataset, we showed that the XBP1 transcription was significantly decreased in thyroid cancer (TC) tissues with lymph node metastasis as compared to that without lymph node metastasis. Moreover, we also found that XBP1 expression was significantly correlated with patients’ gender, T classification, lymph node metastasis and PTC stages, and low XBP1 expression was associated with poor diseases free survival (DFS). In vitro, XBP1s overexpression could inhibit the invasion, migration, and wound healing capacity of PTC cells. Mechanistically, overexpression of XBP1s could enhance the expression of classical epithelial–mesenchymal transition (EMT) markers such as ZO-1 and E-cadherins, and downregulated N-cadherin in BCPAP cells. Conclusion: These findings suggest that XBP1s is a prognostic maker for thyroid carcinoma patients, and sustaining XBP1s expression might be a new strategy to control PTC progression.

In order to study the transient process of fault current limiter (FCL) based on high coupled split reactor (HCSR) in power system by electromagnetic transient simulation, it is necessary to establish a four-port wideband simulation model of HCSR, which can cover both power frequency and kHz high frequency band. Based on the calculation methods of low-frequency and high-frequency admittance parameters of HCSR, the realization methods of HCSR modeling are reasonably designed, and the modeling method suitable for the wideband modeling of HCSR for FCL is obtained. Firstly, the characteristics of the model and the methods of calculating low-frequency admittance parameters and high-frequency admittance parameters of HCSR are introduced. Secondly, the specific modeling method is introduced in detail, including three main steps: obtaining admittance parameter matrices in the working frequency band (10 Hz-1 MHz) by integration, parameter matrix fitting by vector fitting and passive correction, and establishing equivalent circuit by FDNE component. Finally, taking a HCSR prototype as the object, the prototype model is established using the modeling method, and the correctness of the model is verified, which provides conditions for the transient simulation of FCL.

Purpose: Papillary thyroid cancer (PTC) patients could obtain poor prognosis if they have lymph node metastasis, identification of informative and robust biomarkers for predicting cervical lymph node metastasis is critical for improving clinical decision-making and patient prognosis. Materials and Methods: In this study, we analyzed the expression of X box binding protein 1 spliced-form (XBP1s) in 41 PTC tissue samples and extended our findings using public databases, then we investigated how XBP1s' contributed to PTC progression in vitro. Results: We found that XBP1s' expression was lower in PTC patients with cervical lymph node metastasis than non-metastasis patients by immunohistochemical analysis. With publicly accessible dataset, we showed that the XBP1 transcription was significantly decreased in thyroid cancer (TC) tissues with lymph node metastasis as compared to that without lymph node metastasis. Moreover, we also found that XBP1 expression was significantly correlated with patients' gender, T classification, lymph node metastasis and PTC stages, and low XBP1 expression was associated with poor diseases free survival (DFS). In vitro, XBP1s overexpression could inhibit the invasion, migration, and wound healing capacity of PTC cells. Mechanistically, overexpression of XBP1s could enhance the expression of classical epithelial-mesenchymal transition (EMT) markers such as ZO-1 and E-cadherins, and downregulated N-cadherin in BCPAP cells. Conclusion: These findings suggest that XBP1s is a prognostic maker for thyroid carcinoma patients, and sustaining XBP1s expression might be a new strategy to control PTC progression.

BACKGROUND:Rap1GAP is a tumor suppressor and is downregulated in human malignancies including papillary thyroid cancer (PTC). The mechanism of its suppression in PTC remains unclear.METHODS:Bioinformatic analyses were carried out to evaluate clinical significance and to predict upstream miRNA bindings of Rap1GAP. Three PTC cell lines, TPC-1, B-CPAP, and K1, were employed for functional verification and further experiments. We used dual-luciferase reporter gene assay to confirm the miRNA binding prediction, Western blotting and quantitative polymerase chain reaction (qPCR) to explore miRNA and Rap1GAP regulation, Transwell and wound healing assays to compare cell migration and invasion after protein knockout or overexpression, and Cell Counting Kit-8 (CCK-8) assay to evaluate cell proliferation.RESULTS:Rap1GAP expression was suppressed in thyroid cancer compared to adjacent normal tissues and was a potential diagnostic marker of PTC. Rap1GAP suppression was correlated to younger age, advanced T stage, N stage, extrathyroidal extension, BRAF-like tumors, and higher risk of recurrence. Combined analysis of bioinformatic prediction and dual-luciferase assay revealed binding between miR-3121-3p with 3'UTR of Rap1GAP promoter. MiR-3121-3p promoted cell migration, invasion, and proliferation via inhibiting Rap1GAP and thus upregulating MAPK pathway. Overexpression and knockdown of Rap1GAP could counteract the influence on cell migration and invasion carried out by miR-3121-3p mimic and inhibitor, respectively. Rap1GAP partially impaired the effect of miR-3121-3p in cell growth in the CCK-8 assay.CONCLUSIONS:Rap1GAP expression is suppressed in PTC and is a potential diagnostic marker. Its upstream regulator, miR-3121-3p, affects tumor metastasis and proliferation via regulating Rap1GAP expression. MAPK signaling pathway may be involved in this effect.

AIMS:Psoriasis is a cutaneous disease mainly characterized by keratinocyte hyperproliferation, abnormal epidermal differentiation, inflammation and angiogenesis. In this study, we aimed to report the therapeutic potential of Diosgenin on psoriasis-like models and explore the underlying mechanisms.MAIN METHODS:For in vitro studies, we initially evaluated the bioeffects of Diosgenin on keratinocytes by detecting the cell viability, cell cycle and apoptosis in HaCaT cells. To mimic psoriatic conditions, we established hyperproliferative model by stimulating HaCaT cells with LPS/IL-22 and inflammatory model by LPS/TNF-α stimulation. Meanwhile, differentiation in HaCaT cells and angiogenesis in HUVECs/HMEC-1 were observed. The influence of Diosgenin on above-mentioned conditions was examined. For in vivo studies, we dosed imiquimod (IMQ) -induced mice with Diosgenin and conducted hematoxylin-eosin (HE), TUNEL assay and immunohistochemistry (IHC) to evaluate histological changes, apoptosis and the status of keratinocyte proliferation, epidermal differentiation, vascularity and cutaneous inflammatory cell infiltration respectively.KEY FINDINGS:Results showed that Diosgenin inhibited HaCaT cell growth through cell cycle arrest and NFκB inhibition while induced apoptosis by regulating Caspase3, Bax and Bcl-2 protein expression. After Diosgenin treatment, NFκB nuclear translocation and IL-22 receptor dependent pathways were suppressed in LPS/IL-22 induced HaCaT cells respectively. Furthermore, Diosgenin downregulated proinflammatory cytokines through TLR4/Myd88 inhibition and upregulated several differentiation markers' expression in HaCaT cells. Additionally, Diosgenin inhibited vascular formation partially by reducing the VEGF-α expression in keratinocytes. In animal studies, Diosgenin attenuated psoriatic lesions on mice accordingly.SIGNIFICANCE:This study suggests that Diosgenin might be a promising candidate for developing anti-psoriatic agents.

Endocrine therapy is a systemic therapy and has become the main treatment strategy for patients with estrogen receptor (ER)-positive breast cancer. However, tamoxifen resistance has become an insurmountable clinical challenge, and the underlying mechanisms are still poorly understood. In this study, we explored the roles of CXC chemokine receptor type 4 (CXCR4) in tamoxifen-treated breast cancer and tamoxifen resistance. Based on the Gene Expression Omnibus (GEO) database, high expression of CXCR4 was found to be associated with worse overall survival (hazard ratio [HR] = 4.646, p < 0.001) and cancer-specific survival (HR = 4.480, p < 0.001) in tamoxifen-treated breast cancer. CXCR4 was also positively correlated with the level of AKT phosphorylation and the resistance to tamoxifen in breast cancer. AMD3100 is a CXCR4 antagonist and was found to decrease phosphorylated (p)-AKT levels of tamoxifen-resistant cells. The reversal effect of AMD3100 on tamoxifen resistance was also confirmed in vitro and in vivo. Taken together, our study demonstrated that CXCR4 could be a potential prognostic biomarker for tamoxifen-treated breast cancer, and the combination of AMD3100 with tamoxifen could be a more efficacious therapeutic strategy for the treatment of tamoxifen resistance.

Background: Endocrine therapy plays a key role in estrogen receptor-positive breast cancer patients; but, tamoxifen resistance could be a real difficulty for these patients. Several attempts have been made to explore the mechanism and new therapies for these patients. We intend to clarify the expression change of SRC and SIRT1 in tamoxifen-resistant breast cancer cells and explore their functions on tamoxifen resistance. Methods: SRC and SIRT1 expressions were analyzed by RNA sequencing, qPCR and Western blotting. Loss and gain of function of SRC and SIRT1 were utilized to indicate their oncogenic roles in tamoxifen resistance in vitro and in vivo. Kaplan-Meier analysis and receiver operating characteristic curve were used to evaluate the survival and the predicted effects of SRC and SIRT1 on patients' prognosis. Results: High expressions of SRC and/or SIRT1 were found in tamoxifen-resistant cells and related to poor overall survival (p<0.05 for SRC, p<0.001 for SIRT1, p<0.001 for SRC and SIRT1) and cancer-specific survival (p<0.05 for SRC, p<0.01 for SIRT1, p<0.01 for SRC and SIRT1) of tamoxifen-treated breast cancer patients. Down-regulation of SRC (p<0.01) or SIRT1 (p<0.05) separately reversed the resistance to tamoxifen and the minimal concentration of SRC inhibitor KX-01 (p<0.05) or SIRT1 inhibitor EX527 (p<0.001) could also suppress cell proliferation. The expression level of SIRT1 was positively correlated with that of SRC. Overexpression of SRC significantly promotes the cell resistance to tamoxifen inhibited by SIRT1 (p<0.01). In vivo experiments confirmed the effects of SRC on tumor growth by over- or down-regulating SRC expression (p<0.001 and p<0.001, respectively). Conclusion: SRC and SIRT1 are both up-regulated in tamoxifen-resistant breast cancer cells and related to a poor prognosis in tamoxifen-treated breast cancer. Moreover, SRC could promote tamoxifen resistance by up-regulating SIRT1. SRC and SIRT1 might be novel therapeutic targets in tamoxifen-resistant breast cancer and the interaction between SRC and SIRT1 needs to be further explored.

Background: Thyroid cancer is one of the most prevalent endocrine cancers with a rising incidence rate over the past years. Papillary thyroid cancer (PTC) is the dominant historical type of thyroid cancer. Early lymph node metastasis happens frequently in PTC. However, some of the lymph node metastasis may be troublesome for detecting because of limited methods. Methods: Robust rank aggregation afforded us the shared differential expression genes among multiple datasets. Gene ontology analysis was performed to identify potential functions. Weighted gene co-expression network analysis was used to research the correlations between gene expression patterns with clinical characteristic. Protein-protein interaction network was performed to identify the hub genes. The least absolute shrinkage and selection operator and Logistic regression were performed to construct a prediction model. Results: We developed a three-gene signature prediction model for lymph node metastasis in PTC through transcriptomic analysis. After quality control, we collected 8 microarray datasets from GEO database and an RNA sequencing dataset from TCGA database. We found the transcriptome profiles were correlated with lymph node metastasis and 3 genes were verified to be independent prediction factors towards those statistic approach. Afterwards, we designed a predicable risk score system and effectively confirmed the model in two independent papillary thyroid cancer cohorts. Conclusions: We recommended a successful predicable model of lymph node metastasis in papillary thyroid cancer patients with moderate accuracy.