Association of ADP­ribosylation factor family genes with prognosis and immune infiltration of breast cancer.

Breast cancer (BC) is the most common type of cancer found in women. ADP-ribosylation factors (ARFs) are a group of small proteins that bind to GTP and are involved in controlling different cellular functions. The function and evolution of multiple ARFs in BC have remained to be fully elucidated, despite existing studies on this protein family in Homo sapiens and other species. In the present study, a systematic analysis of ARF expression levels in BC tissues compared to normal breast tissues was performed using data from The Cancer Genome Atlas database. The analysis revealed significantly higher expression of ARFs in BC tissues. In addition, the prognostic significance of ARF1 and ARF3-6 expression levels was assessed in patients with BC. Of note, elevated ARF1 expression was associated with reduced rates of distant metastasis-free survival (DMFS), overall survival (OS) and recurrence-free survival (RFS) in affected individuals. Similarly, patients with high expression levels of ARF3 had lower post-progression survival (PPS) rates. In addition, patients with higher ARF4 expression had worse PPS and patients with high ARF5 expression exhibited lower DMFS. Patients with high ARF6 expression had worse DMFS, OS, RFS and predictive power score values. Furthermore, the expression of ARF was found to be strongly linked to the infiltration of various immune cell types, namely dendritic cells, macrophages, neutrophils, CD8+ T cells and B cells. These significant associations offer a solid foundation for the potential utilization of new therapeutic targets and predictive markers for the treatment of BC.

A new prediction nomogram of non-sentinel lymph node metastasis in cT1-2 breast cancer patients with positive sentinel lymph nodes.

We aimed to analyze the risk factors and construct a new nomogram to predict non-sentinel lymph node (NSLN) metastasis for cT1-2 breast cancer patients with positivity after sentinel lymph node biopsy (SLNB). A total of 830 breast cancer patients who underwent surgery between 2016 and 2021 at multi-center were included in the retrospective analysis. Patients were divided into training (n = 410), internal validation (n = 298), and external validation cohorts (n = 122) based on periods and centers. A nomogram-based prediction model for the risk of NSLN metastasis was constructed by incorporating independent predictors of NSLN metastasis identified through univariate and multivariate logistic regression analyses in the training cohort and then validated by validation cohorts. The multivariate logistic regression analysis revealed that the number of positive sentinel lymph nodes (SLNs) (P < 0.001), the proportion of positive SLNs (P = 0.029), lymph-vascular invasion (P = 0.029), perineural invasion (P = 0.023), and estrogen receptor (ER) status (P = 0.034) were independent risk factors for NSLN metastasis. The area under the receiver operating characteristics curve (AUC) value of this model was 0.730 (95% CI 0.676-0.785) for the training, 0.701 (95% CI 0.630-0.773) for internal validation, and 0.813 (95% CI 0.734-0.891) for external validation cohorts. Decision curve analysis also showed that the model could be effectively applied in clinical practice. The proposed nomogram estimated the likelihood of positive NSLNs and assisted the surgeon in deciding whether to perform further axillary lymph node dissection (ALND) and avoid non-essential ALND as well as postoperative complications.

Role of glutaminyl-peptide cyclotransferase in breast cancer doxorubicin sensitivity.

Doxorubicin (DOX) is one of the most effective and widely used chemotherapeutic drugs. However, DOX resistance is a critical risk problem for breast cancer treatment. Previous studies have demonstrated that metadherin (MTDH) involves in DOX resistance in breast cancer, but the exact mechanism remains unclear. In this study, we found that glutaminyl-peptide cyclotransferase (QPCT) was a MTDH DOX resistance-related downstream gene in breast cancer. Elevated expression of QPCT was found in the GEPIA database, breast cancer tissue, and breast cancer cells. Clinical data showed that QPCT expression was positively associated with poor prognosis in DOX-treated patients. Overexpression of QPCT could promote the proliferation, invasion and migration, and reduce DOX sensitivity in MCF-7 and MDA-MB-231 cells. Mechanistically, MTDH positively regulates the expressions of NF-κB (p65) and QPCT, and NF-κB (p65) directly regulates the expression of QPCT. Therefore, MTDH/NF-κB (p65)/QPCT signal axis was proposed. Collectively, our findings delineate the mechanism by which the MTDH/NF-κB (p65) axis regulate QPCT signaling and suggest that this complex may play an essential role in breast cancer progression and affect DOX sensitivity.

Metabolomics and transcriptomics of embryonic livers reveal hypoxia adaptation of Tibetan chickens.

BACKGROUND: Exploring the hypoxia adaptation mechanism of Tibetan chicken is of great significance for revealing the survival law of Tibetan chicken and plateau animal husbandry production. To investigate the hypoxia adaptation of Tibetan chickens (TBCs), an integrative metabolomic-transcriptomic analysis of the liver on day 18 of embryonic development was performed. Dwarf laying chickens (DLCs), a lowland breed, were used as a control. RESULTS: A total of 1,908 metabolites were identified in both TBCs and DLCs. Energy metabolism and amino acid metabolism related differentially regulated metabolites (DRMs) were significantly enriched under hypoxia. Important metabolic pathways including the TCA cycle and arginine and proline metabolism were screened; PCK1, SUCLA2, and CPS1 were found to be altered under hypoxic conditions. In addition, integrated analysis suggested potential differences in mitochondrial function, which may play a crucial role in the study of chicken oxygen adaptation. CONCLUSIONS: These results suggest that hypoxia changed the gene expression and metabolic patterns of embryonic liver of TBCs compared to DLCs. Our study provides a basis for uncovering the molecular regulation mechanisms of hypoxia adaptation in TBCs with the potential application of hypoxia adaptation research for other animals living on the Qinghai-Tibet plateau, and may even contribute to the study of diseases caused by hypoxia.

Bioinformatic analysis reveals an association between Metadherin with breast cancer prognosis and tumor immune infiltration.

Breast cancer metastasis and invasion are both promoted by the oncoprotein Metadherin (MTDH). However, the the role of Metadherin in breast cancer progression and its role in the immune microenvironment. Are not clear. A bioinformatic analysis was performed to demonstrate the prognostic value of Metadherin in BC. In the present study, we found that Metadherin is overexpressed in BC and is significantly correlated with individual cancer stage, age, subclasses, menopause and nodal metastasis status. Metadherin overexpression was associated with a significant decrease in OS and DSS. Cox multivariate analysis indicated that Metadherin was an independent negative prognostic indicator for OS and DSS. Moreover, Metadherin hypomethylation status was associated with poor prognosis. A negative correlation was also noted between Metadherin overexpression and the number of plasmacytoid dendritic cells, cluster of differentiation 8+ T cells, and natural killer cells. Association patterns varied with different subtypes. Various associations between Metadherin levels and immune cell surface markers were revealed. A total of 40 groups of BC and adjacent normal breast tissue samples were collected. Metadherin mRNA was detected by PCR, and its expression levels in BC tissues were significantly increased compared with those noted in normal tissues. The expression levels of Metadherin were also measured in normal and BC cell lines, respectively, and similar conclusions were obtained. The Metadherin mRNA levels were knocked down in SK-BR3 and MDA-MB-231 cell lines and the cell proliferative and migratory activities were determined using Cell Counting Kit-8 and scratch assays, respectively. The results indicated that the cell proliferative and migratory abilities were reduced following knockdown of Metadherin expression. Therefore, Metadherin may be considered as a novel prognostic biomarker in BC.

Metadherin inhibits chemosensitivity of triple-negative breast cancer to paclitaxel via activation of AKT/GSK-3ß signaling pathway.

Triple-negative breast cancer (TNBC) has an aggressive clinical course, and paclitaxel (PTX)-based chemotherapy remains the main therapeutic drug. Metadherin (MTDH) acts as an oncogene that regulates proliferation, invasion, metastasis, and chemoresistance. This study aimed to investigate whether TNBC chemosensitivity to PTX was related to the MTDH/AKT/glycogen synthase kinase-3beta (GSK-3ß) pathway. Clinical baseline characteristics and immunohistochemistry (IHC) were used to evaluate the expression and prognosis of MTDH and AKT (protein kinase B, PKB) in TNBC patient samples. MTDH shRNA, MTDH overexpression vector, MK-2206, and PTX intervention were used in cell models and mouse tumor-bearing models. Afterwards, mRNA and protein levels were assessed using quantitative real-time polymerase chain reaction and Western blot. Evaluate the level of tumor cell apoptosis and cell cycle using flow cytometry. Cell viability was detected using Cell Count Kit 8. The in vivo imaging system is used to analyze the growth of tumors. We found that higher expression of MTDH or AKT resulted in poorer disease-free survival and a lower Miller-Payne grade. MTDH promotes cell proliferation and increases p-AKT and p-GSK-3ß expression in TNBC cells. Notably, suppression of AKT terminated MTDH overexpression-induced cell proliferation and apoptosis. MTDH knockdown or the AKT inhibitor MK2206 reduced the p-AKT and p-GSK-3ß ratio, reduced cell viability and proliferation, increased cell apoptosis, and increased chemosensitivity to PTX. In vivo, xenograft tumors of an MTDH knockdown+MK2206 group treated with PTX were the smallest compared to other groups. In short, MTDH inhibits TNBC chemosensitivity to PTX by activating the AKT/GSK-3ß signaling pathway.

Comprehensive analysis of ACKR family members in breast cancer using prognostic values.

Breast cancer (BC) is by far the most prevalent malignancy found in the female population. Atypical chemokine receptors (ACKRs) are a subclass of G-protein-coupled receptors, which are characterized by disrupted ligand binding and a breakdown of signaling following ligand binding. The evolution and function of multiple ACKRs in BC have yet to be fully elucidated, although certain findings on this family have been reported in several studies in Homo sapiens and other species. The present study identified that the expression level of ACKRs was significantly lower in breast carcinoma (BRCA) tissues compared with normal breast tissues through searches of the Tumor Immune Estimation Resource, UALCAN and Gene Expression Profiling Interactive Analysis databases. Additionally, when comparing BRCA tissues with normal breast tissues, it was found that there was obvious hypomethylation in the promoters of ACKR1, ACKR3 and ACKR5, as well as a marked hypermethylation in the promoters of ACKR2 and ACKR6. In determining the prognosis of patients with BRCA, the expression levels of ACKR1, ACKR2, ACKR3, ACKR4 and ACKR6 were all found to be important factors. The values for distant metastasis-free survival (DMFS), overall survival (OS) and recurrence-free survival (RFS) were all found to be lower in patients with BRCA who had a low expression level of ACKR1. In addition, the RFS rates for patients with BRCA were lower when the expression of ACKR2 was low, and worse values for DMFS, OS and RFS were found to be highly correlated with higher expression levels of ACKR3. Moreover, the DMFS, OS, RFS and predictive power score values were worse in those patients with low ACKR4 expression, and the RFS values for patients with BRCA were also found to be lower when the expression level of ACKR6 was low. Additionally, dendritic cells, macrophages, neutrophils, T cells with CD4+ status, T cells with CD8+ status and B cells were all substantially linked with ACKR expression, as well as immune cell infiltration. Taken together, the findings of the present study may offer a theoretical foundation for the creation of novel targets and prognostic indicators for BRCA therapy.

Integrated analysis of FKBP1A/SLC3A2 axis in everolimus inducing ferroptosis of breast cancer and anti-proliferation of T lymphocyte.

Background: Solute Carrier Family 3 Member 2 (SLC3A2) is a member of the solute carrier family that plays pivotal roles in regulation of intracellular calcium levels and transports L-type amino acids. However, there are insufficient scientific researches on the prognostic and immunological roles of SLC3A2 in breast cancer (BC) and whether everolimus regulates novel SLC3A2 related molecular mechanism in the immuno-oncology context of the tumor microenvironment (TME), therefore, we see a necessity to conduct the current in silico and biological experimental study. Methods: Using diverse online databases, we investigated the role of SLC3A2 in therapy response, clinicopathological characteristics, tumor immune infiltration, genetic alteration, methylation and single cell sequencing in BC. WB, Co-IP, cell proliferation assay, Edu staining, ROS and GSH assay and in vivo tumor xenograft assays were performed to verify FKBP1A/SLC3A2 axis in everolimus inducing ferroptosis of breast cancer. Co-cultures and IL-9 ELISA were performed to demonstrate the T lymphocyte function. Results: We demonstrated that SLC3A2 was aberrantly expressed among various BC cohorts. Our results also suggested that SLC3A2 expression was associated with chemotherapeutic outcome in BC patients. Our results further indicated that SLC3A2 was associated with tumor infiltration of cytotoxic T cell but not other immune cells among BC TME. The alterations in SLC3A2 gene had a significant correlation to relapse free survival and contributed a significant impact on BC tumor mutational burden. Finally, SLC3A2 was illustrated to be expressed in diverse BC cellular populations at single cell level, and negatively linked to angiogenesis, inflammation and quiescence, but positively correlated with other functional phenotypes. Noteworthily, everolimus (a targeted therapy drug for BC) related protein, FK506-binding protein 1A (FKBP1A) was found to bind with SLC3A2, and negatively regulated SLC3A2 expression during the processes of everolimus inducing ferroptosis of BC cells and promoting anti-proliferation of Th9 lymphocytes. Conclusions: Altogether, our study strongly implies that SLC3A2 is an immuno-oncogenic factor and FKBP1A/SLC3A2 axis would provide insights for a novel immunotherapy approach for the treatment of BC in the context of TME.

A negative feedback loop between KLF9 and the EMT program dictates metastasis of hepatocellular carcinoma.

Metastasis is the primary cause of death of hepatocellular carcinoma (HCC), while the mechanism underlying this severe disease remains largely unclear. The Kruppel-like factor (KLF) family is one of the largest transcription factor families that control multiple physiologic and pathologic processes by governing the cellular transcriptome. To identify metastatic regulators of HCC, we conducted gene expression profiling on the MHCC97 cell series, a set of subclones of the original MHCC97 that was established by in vivo metastasis selection therefore harbouring differential metastatic capacities. We found that the expression of KLF9, a member of the KLF family, was dramatically repressed in the metastatic progeny clone of the MHCC97 cells. Functional studies revealed overexpression of KLF9 suppressed HCC migration in vitro and metastasis in vivo, while knockdown of KLF9 was sufficient to promote cell migration and metastasis accordingly. Mechanistically, we found the expression of KLF9 can reverse the pro-metastatic epithelial-mesenchymal transition (EMT) program via direct binding to the promoter regions of essential mesenchymal genes, thus repressing their expression. Interestingly, we further revealed that KLF9 was, in turn, directly suppressed by a mesenchymal transcription factor Slug, suggesting an intriguing negative feedback loop between KLF9 and the EMT program. Using clinical samples, we found that KLF9 was not only downregulated in HCC tissue compared to its normal counterparts but also further reduced in the HCC samples of whom had developed metastatic lesions. Together, we established a critical transcription factor that represses HCC metastasis, which is clinically and mechanically significant in HCC therapies.

​Efficacy and safety of pyrotinib in combination with albumin­bound paclitaxel for the treatment of HER2­positive advanced breast cancer: A real­world study.

The present study aimed to determine the efficacy and safety of pyrotinib in combination with albumin-bound paclitaxel in patients with HER2-positive advanced breast cancer (ABC). A total of 48 patients diagnosed with HER2-positive ABC were included in the present study, and these patients were prescribed a combination of pyrotinib and albumin-bound paclitaxel in routine clinical practice. During a 21-day cycle, the standard dosage of pyrotinib was 400 mg single dose/day, which was administered orally, and 130 mg/m2/day albumin-bound paclitaxel on days 1, 8 and 15, which was administered by intravenous drip. The primary efficacy endpoint was progression-free survival (PFS) and the secondary efficacy endpoint was overall response rate (ORR), which was defined as the percentage of patients with complete remission or partial remission. Safety indicators were also observed in the present study. The results of the present study demonstrated that the median PFS (mPFS) was 8.1 months for all patients, ranging from 3.3-10.6 months. Patients receiving pyrotinib as second-line therapy exhibited a longer mPFS of 8.5 months compared with those receiving it as third- or higher-line therapy (mPFS, 5.9 months). In 17 patients with brain metastases, mPFS was 7.3 months, ranging from 4.8-10.1 months. The results of the present study also demonstrated that the ORR for the 48 patients was 33.3%. Notably, diarrhea was the most common grade 3-4 adverse event, occurring in 22.9% of patients, followed by neutropenia (6.3%), leukopenia (4.2%) and anemia (4.2%). Collectively, the results of the present study indicated that pyrotinib-based treatment is effective for patients with HER2+ ABC, including those who have previously been treated with trastuzumab. Thus, the combination of pyrotinib with albumin-bound paclitaxel is recommended due to high levels of efficacy, convenience and tolerability.

Obesity and its impact on female reproductive health: unraveling the connections.

In the modern era, the escalating global prevalence of obesity has profound implications on female reproductive health. Obesity, transcending mere lifestyle choices, has evolved into a complex disorder affecting physiological and metabolic functions. Concurrently, female infertility is rising as a significant global health issue. Obesity, with its extensive systemic effects, is pinpointed as a major disruptor. The convergence of these health challenges reveals a multifaceted scenario: on one hand, obesity directly impacts female reproductive health, particularly in the context of conditions like polycystic ovary syndrome (PCOS) and menstrual disturbances; on the other, the psychosocial consequences of infertility might intensify weight-gain patterns, forming a challenging cycle. Additionally, the economic implications of treating obesity-related infertility are considerable. This review delves into the myriad ways obesity affects female reproductive health, drawing insights from epidemiological, clinical, and molecular studies. It explores the epidemiological relationship between obesity and PCOS, the influence of obesity on menstrual disturbances, and the broader impact of obesity on female infertility. Weight loss, through pharmacological interventions, surgical methods, or lifestyle adjustments, emerges as a promising strategy. Lastly, the efficacy of assisted reproductive technologies, such as IVF, is influenced by obesity, underscoring the importance of an optimal body mass index. The review also highlights the molecular and physiological mechanisms underlying the impact of obesity on female reproductive health, including the disruption of the hypothalamic-pituitary-ovary axis, altered adipokine secretion, and the role of chronic inflammation and oxidative stress.

Pathological online game use of secondary vocational school students: Current situation and its relation to self-esteem and self-identity.

Secondary Vocational School Students are particularly susceptible to online game addiction due to adolescent characteristics and superimposed pressures of academic and employment. Based on the theoretical framework of self-identity and self-esteem, the present research conducted a questionnaire survey using samples of secondary vocational school students to investigate the relationship between pathological online game use (POGU), self-esteem and self-identity. The results showed that 15.56% of secondary vocational students' level of POGU met the diagnostic criteria, and POGU and self-esteem appeared significant differences in gender and family types. Moreover, lower self-esteem and self-identity were associated with higher POGU and self-esteem played a partial mediating role in the relationship between self-identity and POGU. We briefly discussed practical implications of our findings and the future research.

miR-217-5p suppresses epithelial-mesenchymal transition and the NF-κB signaling pathway in breast cancer via targeting of metadherin.

MicroRNAs (miRNAs) have been associated with a number of human malignancies, including breast cancer (BC). However, the expression, biological function and fundamental underlying mechanism of miR-217-5p in BC remain unclear. Therefore, in the present study, the expression levels of miR-217-5p and metadherin (MTDH) were examined in BC tissues and BC cell lines using reverse transcription-quantitative PCR. Cell Counting Kit-8 assays, cell proliferation, wound healing assays, Transwell assays and western blotting were used to examine the effects of miR-217-5p on cell proliferation, migration, the epithelial-mesenchymal transition (EMT) and NF-κB signaling pathway expression. The direct relationship between miR-217-5p and MTDH was assessed using a dual-luciferase reporter assay. The results demonstrated that significantly reduced expression levels of miR-217-5p but significantly increased mRNA expression levels of MTDH were observed in BC tissues from 35 patients with BC compared with non-tumor breast tissues. Furthermore, BC cell lines SK-BR3 and BT549 expressed miR-217-5p at markedly lower levels and MTDH at markedly higher levels compared with the breast epithelial MCF10A cell line. miR-217-5p overexpression significantly inhibited cell proliferation, invasion and migration and suppressed the EMT in BC cells. miR-217-5p overexpression also inhibited the NF-κB signaling pathway by markedly decreasing p65 mRNA and protein expression levels but significantly increasing IκBα expression levels. Furthermore, miR-217-5p knockdown markedly increased MTDH mRNA and protein expression levels. The expression levels of miR-217-5p were negatively correlated with those of MTDH in BC tissues. These results suggested that restoration of MTDH expression levels could potentially attenuate the inhibitory effects of miR-217-5p overexpression on BC cell proliferation. Therefore, in conclusion miR-217-5p overexpression may inhibit cell migration, invasion, the EMT and NF-κB signaling pathway in BC via targeting of MTDH. miR-217-5p may serve as an important potential target in BC therapy.

Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth.

Tumors can reprogram the functions of metabolic enzymes to fuel malignant growth; however, beyond their conventional functions, key metabolic enzymes have not been found to directly govern cell mitosis. Here, we report that glutamine synthetase (GS) promotes cell proliferation by licensing mitotic progression independently of its metabolic function. GS depletion, but not impairment of its enzymatic activity, results in mitotic arrest and multinucleation across multiple lung and liver cancer cell lines, patient-derived organoids and xenografted tumors. Mechanistically, GS directly interacts with the nuclear pore protein NUP88 to prevent its binding to CDC20. Such interaction licenses activation of the CDC20-mediated anaphase-promoting complex or cyclosome to ensure proper metaphase-to-anaphase transition. In addition, GS is overexpressed in human non-small cell lung cancer and its depletion reduces tumor growth in mice and increases the efficacy of microtubule-targeted chemotherapy. Our findings highlight a moonlighting function of GS in governing mitosis and illustrate how an essential metabolic enzyme promotes cell proliferation and tumor development, beyond its main metabolic function.

Transcriptional Control of Metastasis by Integrated Stress Response Signaling.

As a central cellular program to sense and transduce stress signals, the integrated stress response (ISR) pathway has been implicated in cancer initiation and progression. Depending on the genetic mutation landscape, cellular context, and differentiation states, there are emerging pieces of evidence showing that blockage of the ISR can selectively and effectively shift the balance of cancer cells toward apoptosis, rendering the ISR a promising target in cancer therapy. Going beyond its pro-survival functions, the ISR can also influence metastasis, especially via proteostasis-independent mechanisms. In particular, ISR can modulate metastasis via transcriptional reprogramming, in the help of essential transcription factors. In this review, we summarized the current understandings of ISR in cancer metastasis from the perspective of transcriptional regulation.

No association between serum uric acid and lumbar spine bone mineral density in US adult males: a cross sectional study.

Available evidence linking serum uric acid (SUA) and bone mineral density (BMD) remains controversial, and data on this association are limited among adult men in the general population. Thus, the aim of this study was to evaluate the association of SUA with lumbar spine BMD in US adult males. A cross-sectional study was conducted based on the National Health and Nutrition Examination Survey (NHANES, 1999-2006) database. Multivariate linear regression analyses were employed to assess the association of SUA with lumbar spine BMD, considering complex survey design and sampling weights. Through rigorous eligibility criteria, a total of 6704 individuals were yielded for final data analysis (average age, 40.5 years; 70.6% white). After fully adjusting potential confounders, no associations were detected between SUA and lumbar spine BMD [ß (95% confidence interval, CI), - 0.003 (- 0.007, 0.002)]. Additionally, similar results were observed in all stratification analyses, and no interactions were found based on all priori specifications. In brief, our findings did not provide an inspiring clue for the hypothesis that SUA may be beneficial to lumbar spine BMD. Future more prospective studies are needed to further explore the causal relationship of SUA with lumbar spine BMD.

EGFR TKIs impair lysosome-dependent degradation of SQSTM1 to compromise the effectiveness in lung cancer.

Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR TKIs) greatly improved clinical outcomes of patients with non-small cell lung cancer (NSCLC). Unfortunately, primary and acquired resistance limits their clinical benefits. To overcome such resistance, new generations of EGFR TKIs have been developed by targeting newly identified mutations in EGFR. However, much less effort has been put into alternative strategies, such as targeting the intrinsic protective responses to EGFR TKIs. In this study, we found that EGFR TKIs, including gefitinib and AZD9291, impaired lysosome-dependent degradation of SQSTM1, thus compromising their anti-cancer efficiency. By accumulating in the lysosome lumen, gefitinib and AZD9291 attenuated lysosomal acidification and impaired autolysosomal degradation of SQSTM1 owing to their intrinsic alkalinity. As a result, SQSTM1 protein was stabilized in response to gefitinib and AZD9291 treatment and conferred EGFR TKI resistance. Depleting SQSTM1 significantly increased the sensitivity of NSCLC cells to gefitinib and AZD9291 both in vitro and in vivo. Furthermore, a chemically modified gefitinib analog lacking alkalinity displayed stronger inhibitory effects on NSCLC cells. Therefore, targeting accumulated SQSTM1 or chemically modified EGFR TKIs may represent new strategies to increase the effectiveness of EGFR targeted therapy.

Long non-coding RNAs involved in autophagy regulation.

Autophagy degrades non-functioning or damaged proteins and organelles to maintain cellular homeostasis in a physiological or pathological context. Autophagy can be protective or detrimental, depending on its activation status and other conditions. Therefore, autophagy has a crucial role in a myriad of pathophysiological processes. From the perspective of autophagy-related (ATG) genes, the molecular dissection of autophagy process and the regulation of its level have been largely unraveled. However, the discovery of long non-coding RNAs (lncRNAs) provides a new paradigm of gene regulation in almost all important biological processes, including autophagy. In this review, we highlight recent advances in autophagy-associated lncRNAs and their specific autophagic targets, as well as their relevance to human diseases such as cancer, cardiovascular disease, diabetes and cerebral ischemic stroke.

Tamoxifen activates Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia.

Long-term application of Tamoxifen (TAM) is usually recommended for hormone receptor positive breast cancer patients. Unfortunately, TAM will inevitably increase the incidence of endometrial hyperplasia even endometrial cancer. Despite of substantial investigations, no effective approaches to prevent TAM-induced endometrial carcinogenesis have been acknowledged. In this study, we found that inhibition of Nrf2 could be valuable to prevent TAM-induced endometrial hyperplasia. Upon TAM treatment, the mRNA and protein expression of autophagy adaptor SQSTM1 was specifically increased in endometrial cells but not breast cancer cells. Knocking-down of SQSTM1 expression retarded TAM-promoted growth of endometrial cancer cells. TAM stimulated SQSTM1 transcription specifically in endometrial cells by enhancing phosphorylation and nuclear translocation of Nrf2. Indeed, the expression of Nrf2 and SQSTM1 were positively correlated in primary endometrial tissues. In rats with TAM-induced endometrial hyperplasia, both Nrf2 and SQSTM1 expression were increased. Nrf2 inhibitor brusatol effectively attenuated TAM-induced SQSTM1 upregulation and endometrial hyperplasia. The kinase of Nrf2, PRKCD, was activated by TAM. Once PRKCD was depleted, TAM failed to promote Nrf2 phosphorylation and SQSTM1 expression. In summary, TAM stimulated Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia by activating PRKCD. Therefore, blocking PRKCD-Nrf2-SQSTM1 signaling could be useful to prevent TAM-induced endometrial hyperplasia.