ER-α36 is involved in calycosin inhibition of IL-6 production in macrophages.

The tumour microenvironment (TME) is crucial for tumour development and progression. Tumour-associated macrophages (TAMs) in the TME can promote tumour progression and metastasis by releasing cytokines, such as IL-6. Calycosin, a phytoestrogen that is one of the active compounds in Radix Astragali, has been shown to inhibit tumour growth and metastasis. However, the underlying mechanism by which calycosin inhibits tumour growth remains unclear. Thus, this study aimed to investigate the effect of calycosin on IL-6 production in peripheral blood mononuclear cell (PBMC)- and THP-1-derived macrophages and explore its potential mechanisms using co-immunoprecipitation, western blotting, immunofluorescence, chromatin immunoprecipitation and luciferase assays. We found that calycosin treatment substantially upregulated the expression of ER-α36, a variant of the ER, and reduced IL-6 production in macrophages. Mechanistically, ER-α36 physically interacted with NF-κBp65 and retained p65 in the cytoplasm to attenuate NF-κB function as an IL-6 transcriptional inducer. In conclusion, our result indicated that calycosin inhibited IL-6 production by enhancing ER-α36 expression and its interaction with p65, which attenuated NF-κB function as an IL-6 inducer. Therefore, calycosin can be developed as an effective agent for cancer therapy by targeting TAMs.

Involvement of the OTUB1-YAP1 axis in driving malignant behaviors of head and neck squamous cell carcinoma.

BACKGROUND: Comprehending the molecular mechanisms underlying head and neck squamous cell carcinoma (HNSCC) is vital for the development of effective treatment strategies. Deubiquitinating enzymes (DUBs), which regulate ubiquitin-dependent pathways, are potential targets for cancer therapy because of their structural advantages. Here we aimed to identify a potential target for HNSCC treatment among DUBs. METHODS: A screening process was conducted using RNA sequencing data and clinical information from HNSCC patients in the TCGA database. A panel of 88 DUBs was analyzed to identify those associated with poor prognosis. Subsequently, HNSCC cells were modified to overexpress specific DUBs, and their effects on cell proliferation and invasion were evaluated. In vivo experiments were performed to validate the findings. RESULTS: In HNSCC patients, USP10, USP14, OTUB1, and STAMBP among the screened DUBs were associated with a poor prognosis. Among them, OTUB1 showed the most aggressive characteristics in both in vitro and in vivo experiments. Additionally, OTUB1 regulated the stability and nuclear localization of YAP1, a substrate involved in cell proliferation and invasion. Notably, OTUB1 expression exhibited a positive correlation with the HNSCC-YAP score in HNSCC cells. CONCLUSIONS: This study highlights the critical role of OTUB1 in HNSCC progression via modulating YAP1. Targeting the OTUB1-YAP1 axis holds promise as a potential therapeutic strategy for HNSCC treatment.

[Retracted] Expression of USP22 and Survivin is an indicator of malignant behavior in hepatocellular carcinoma.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that a pair of data panels showing the results of immunohistochemical staining experiments in Fig. 1 on p. 2210 had already appeared in a previously published paper (Zhang Y, Li Y, Lin C, Ding J, Liao G and Tang B: Aberrant upregulation of 14­3­3σ and EZH2 expression serves as an inferior prognostic biomarker for hepatocellular carcinoma. PLos ONE 9: e107251, 2014).  Owing to the fact that the contentious data in the above article had already been published prior to its submission to International Journal of Oncology, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 47: 2208­2216, 2015; DOI: 10.3892/ijo.2015.3214].

Combined effects of vitamin D and neferine on the progression and metastasis of colorectal cancer.

PURPOSE: To investigate the synergistic effect of vitamin D and neferine on the growth and metastasis of colorectal cancer (CRC). METHODS: The synergistic effect of biologically active form of vitamin D, VD3 and neferine on the treatment of CRC was investigated by bliss analysis. Colony formation and wound healing ability, migration and invasion ability, and epithelial mesenchymal transition of HCT-116 cells, as a response to the combination treatment with VD3 and neferine were evaluated. RESULTS: VD3 and neferine showed a synergistic effect on CRC cell growth at a relatively low dose. The wound healing and colony formation capacity, cell migration and invasion abilities were all decreased by combination use of VD3 and neferine, compared to the VD3 or neferine treated single group. Furthermore, VD3 and neferine significantly decreased the expressions of N-cadherin, vimentin, snail, and slug in HCT-116 cells. CONCLUSION: These data suggest that neferine enhances the anticancer capability of VD3 and reduces the dose dependency of VD3. The combination of vitamin D with neferine appears to be a potential therapeutic strategy for CRC.

HOXA5 inhibits the proliferation and metastasis of cervical squamous cell carcinoma by suppressing the ß-catenin/Snail signaling.

HOXA5, as a transcription factor, plays an important role in a variety of malignant tumors. Nevertheless, its biological role in cervical squamous cell carcinoma (CSCC) is largely unknown. In our study, we aimed to explore the function of HOXA5 in CSCC and its molecular mechanism. Immunohistochemistry showed that HOXA5 expression was downregulated in human CSCC tissues and HOXA5 staining was negatively correlated with tumor size and histological grade of CSCC. Ectopic expression of HOXA5 inhibited proliferative and metastatic abilities of CSCC cells in vitro and in vivo. Furthermore, overexpression of HOXA5 inhibited the cell cycle by arresting the S/G2 phase by flow cytometry and that was related to the downregulation of Cyclin A. Further study showed that HOXA5 suppressed EMT by inhibiting the ß-catenin/Snail signaling resulting in reduced metastasis of CSCC cells. Altogether, our results suggested that HOXA5 inhibited the proliferation and metastasis via repression of the ß-catenin/Snail pathway, proposing the potential role of HOXA5 in the prevention and treatment of CSCC.

Depletion of PARP10 inhibits the growth and metastatic potential of oral squamous cell carcinoma.

Background: Although poly (ADP-ribose) polymerase family member 10 (PARP10) has been implicated in the progression of multiple cancer types, its role in oral squamous cell carcinoma (OSCC) remains unknown. This study aimed to examine the function of PARP10 in OSCC and investigate the underlying mechanisms. Methods: The expression of PARP10 in OSCC was investigated in OSCC patient cohorts. Kaplan-Meier curve analysis was performed to assess the association between PARP10 and prognosis in OSCC. Correlation between PARP10 expression and the related variables was analyzed by χ2 test. CKK-8, transwell assay, western blot, immunohistochemistry, immunofluorescence, and bioinformatic analysis, were applied to clarify the role of PARP10 in OSCC. Results: PARP10 was found to be markedly elevated in OSCC tissues. The upregulation of PARP10 predicted shorter overall survival and disease-specific survival and was significantly correlated with several malignant features. Moreover, depletion of PARP10 markedly inhibited the proliferation, migration, and invasion of OSCC cells, and promoted OSCC cell apoptosis, and resulted in alterations of relevant proteins. Furthermore, a positive correlation was observed between the expression of PARP10 and Ki67, PARP1, MMP2, and VEGF. In addition, depletion of PARP10 impaired the PI3K-AKT and MAPK signaling pathways. Conclusion: PARP10 is involved in the progression of OSCC via regulation of PI3K-AKT and MAPK signaling pathways.

The role of IL-33/ST2 signaling in the tumor microenvironment and Treg immunotherapy.

Interleukin (IL)-33 is a tissue-derived nuclear cytokine belonging to the IL-1 family. Stimulation-2 (ST2) is the only known IL-33 receptor. ST2 signals mostly on immune cells found within tissues, such as regulatory T cells (Treg cells), CD8+ T cells, and natural killer (NK) cells. Therefore, the IL-33/ST2 signaling pathway is important in the immune system. IL-33 deficiency impairs Treg cell function. ST2 signaling is also increased in active Treg cells, providing a new approach for Treg-related immunotherapy. The IL-33/ST2 signaling pathway regulates multiple immune-related cells by activating various intracellular kinases and factors in the tumor microenvironment (TME). Here, we review the latest studies on the role of the IL-33/ST2 signaling pathway in TME and Treg immunotherapy.

Expression of Ubiquitin-specific protease 7 in oral squamous cell carcinoma promotes tumor cell proliferation and invasion.

Oral Squamous Cell Carcinoma (OSCC) is the most common malignant cancer affecting oral cavity. Recent studies have demonstrated that Ubiquitin-specific protease 7 (USP7) was upregulated in several types of cancers. USP7 expression was associated with various proto-oncogenes and tumor suppressor genes. However, USP7 expression level and its functional role in OSCC is unclear. In the current study, we showed that USP7 expression in OSCC tissues was generally upregulated compared to normal adjacent tissues by using IHC. Furthermore, statistical analysis uncovered that USP7 expression was positively correlated with Ki-67, MMP2, VEGF in OSCC tissues. Importantly, high USP7 expression was significantly correlated with lymph node metastasis and histological differentiation in OSCC patients. So, our hypothesis is that USP7 plays a tumor-promoting role in OSCC. Knocking down of USP7 in tumor cells not only suppressed HSC3 cells proliferation, migration and invasion, but also promoted cell apoptosis. Moreover, USP7 siRNA blocked the activation of Akt/ERK signaling pathway. In conclusion, data presented here suggests that USP7 promotes the progression of OSCC. USP7 may be used as a new therapeutic target for OSCC diagnosis and treatment.

PARP6 suppresses the proliferation and metastasis of hepatocellular carcinoma by degrading XRCC6 to regulate the Wnt/ß-catenin pathway.

PARP6 belongs to the mono-ADP-ribosyltransferase family and has been shown to be involved in the genesis and development of some tumours. However, the role of PARP6 in hepatocellular carcinoma (HCC) development remains to be fully elucidated. In the current study, we demonstrated that PARP6 was expressed at a low level in HCC cells and was negatively related to the degree of tumour differentiation. Additionally, silencing PARP6 led to an increase in the proliferation, invasion and migration ability of HCC cells in both in vitro and in vivo assays. Conversely, an elevation in the PARP6 expression level had the opposite effect. Through gene chip analysis combined with experimental verification, we confirmed that PARP6 can inhibit the expression of XRCC6 by inducing degradation and thus affect the Wnt/ß-Catenin signalling pathway, which contributes to the suppression of HCC. Further mechanistic investigation demonstrated that the ubiquitin ligase HDM2 can interact with PARP6 and XRCC6, and mediated the regulatory effect of PARP6 on XRCC6 degradation. Taking together, PARP6 appears to inhibit HCC progression through the XRCC6/Wnt/ß-catenin signal axis and could be used as a biomarker for the clinical monitoring of HCC development.

Regulatory T cells: A potential weapon to combat COVID-19?

Since the end of December 2019, a novel coronavirus SARS-CoV-2 began to spread, an infection disease termed COVID-19. The virus has spread throughout the world in a short period of time, resulting in a pandemic. The number of reported cases in global reached 5 695 596 including 352 460 deaths, as of May 27, 2020. Due to the lack of effective treatment options for COVID-19, various strategies are being tested. Recently, pathologic studies conducted by two teams in China revealed immunopathologic abnormalities in lung tissue. These results have implications for immunotherapy that could offer a novel therapy strategy for combating lethal viral pneumonia. This review discusses the clinical and pathological features of COVID-19, the roles of immune cells in pathological processes, and the possible avenues for induction of immunosuppressive T regulatory cells attenuating lung inflammation due to viral infection. It is our hope that these proposals may both be helpful in understanding the novel features of SARS-CoV-2 pneumonia as well as providing new immunological strategies for treating the severe sequelae of disease manifestations seen in people infected with SARS-CoV-2.

Human gingiva-derived mesenchymal stem cells are therapeutic in lupus nephritis through targeting of CD39-CD73 signaling pathway.

Cell specific and cytokine targeted therapeutics have underperformed in systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) have emerged as a novel therapy to address the dysregulation in autoimmune diseases but also have limitations. Human gingiva derived MSCs (GMSCs) are superior in regulating immune responses. Here, we demonstrate that the adoptive transfer of GMSCs homes to and maintains in the kidney and has a robust therapeutic effect in a spontaneous lupus nephritis model. Specifically, GMSCs limits the development of autoantibodies as well as proteinuria, decreases the frequency of plasma cells and lupus nephritis histopathological scores by directly suppressing B cells activation, proliferation and differentiation. The blockage of CD39-CD73 pathway dramatically abrogates the suppressive capacities of GMSCs in vitro and in vivo and highlights the significance of this signaling pathway in SLE. Collectively, manipulation of GMSCs provides a promising strategy for the treatment of patients with SLE and other autoimmune diseases.

Correction: JARID1B promotes metastasis and epithelial-mesenchymal transition via PTEN/AKT signaling in hepatocellular carcinoma cells.

[This corrects the article DOI: 10.18632/oncotarget.3713.].

Latexin deficiency in mice up-regulates inflammation and aggravates colitis through HECTD1/Rps3/NF-κB pathway.

The function of Latexin (LXN) in inflammation has attracted attention. However, no data are available regarding its role in colitis. We report that LXN is a suppressor of colitis. LXN deficiency leads to the severity of colitis in DSS-induced mice, and LXN is required for the therapeutic effect of retinoic acid on colitis. Using a proteomics approach, we demonstrate that LXN interacts and forms a functional complex with HECTD1 (an E3 ubiquitin ligase) and ribosomal protein subunit3 (Rps3). IκBα is one of the substrates of HECTD1. Ectopic expression of LXN leads to IκBα accumulation in intestinal epithelial cells, however, LXN knockdown enhances the interaction of HECTD1 and Rps3, contributing to the ubiquitination degradation of IκBα, and subsequently enhances inflammatory response. Thus, our findings provided a novel mechanism underlying LXN modulates colitis via HECTD1/Rps3/NF-κB pathway and significant implications for the development of novel strategies for the treatment of colitis by targeting LXN.

Blended learning in basic medical laboratory courses improves medical students' abilities in self-learning, understanding, and problem solving.

Blended learning, is a teaching approach that integrates online self-learning and classroom teaching. When designed well, blended learning courses in medicine can facilitate students to improve themselves in self-learning, understanding, and problem solving, ultimately enhancing their learning efficiency. However, blended teaching methods are usually used in only a single course, so it is unclear whether these methods can work well in a variety of basic medical courses. The goal of this study is to explore students' perceptions of whether blended laboratory courses are helpful for them in overcoming the difficulties they experience. Blended laboratory courses were taken by medical students at Guilin Medical University. Approximately 71.1% of the students agreed that online lecture courses improved their understanding of threshold concepts and the underlying theories. The majority of the students (63.01%) held the opinion that the blended laboratory courses were more effective than other types of courses in achieving the knowledge goals. The majority of the teachers believed that students' interest in experimentation operations, hands-on abilities, confidence, and other factors were greatly improved compared with those of students taught using the traditional teaching model (face to face). In addition, the average scores for the quizzes of laboratory courses were significantly improved in the blended learning method compared with the traditional learning method. Blended laboratory courses are successful and welcomed by both students and teachers in undergraduate laboratory courses.

PMPCB Silencing Sensitizes HCC Tumor Cells to Sorafenib Therapy.

Hepatocellular carcinoma (HCC) tumors invariably develop resistance to cytotoxic and targeted agents, resulting in failed treatment and tumor recurrence. Previous in vivo short hairpin RNA (shRNA) screening evidence revealed mitochondrial-processing peptidase (PMPC) as a leading gene contributing to tumor cell resistance against sorafenib, a multikinase inhibitor used to treat advanced HCC. Here, we investigated the contributory role of the ß subunit of PMPC (PMPCB) in sorafenib resistance. Silencing PMPCB increased HCC tumor cell susceptibility to sorafenib therapy, decreased liver tumor burden, and improved survival of tumor-bearing mice receiving sorafenib. Moreover, sorafenib + PMPCB shRNA combination therapy led to attenuated liver tumor burden and improved survival outcome for tumor-bearing mice, and it reduced colony formation in murine and human HCC cell lines in vitro. Additionally, PMPCB silencing enhanced PINK1-Parkin signaling and downregulated the anti-apoptotic protein MCL-1 in sorafenib-treated HCC cells, which is indicative of a healthier pro-apoptotic phenotype. Higher pre-treatment MCL-1 expression was associated with inferior survival outcomes in sorafenib-treated HCC patients. Elevated MCL-1 expression was present in sorafenib-resistant murine HCC cells, while MCL-1 knockdown sensitized these cells to sorafenib. In conclusion, our findings advocate combination regimens employing sorafenib with PMPCB knockdown or MCL-1 knockdown to circumvent sorafenib resistance in HCC patients.

Expression of USP22 and the chromosomal passenger complex is an indicator of malignant progression in oral squamous cell carcinoma.

Oral cancer is a common cancer of the head and neck. Oral squamous cell carcinoma (OSCC) represents almost 90% of the total cases of head and neck cancer. Ubiquitin-specific protease 22 (USP22) is a deubiquitinating hydrolase, and it is highly expressed in various types of cancer, which also typically have a poor prognosis. Aurora-B and Survivin, which belong to the chromosomal passenger complex, are also highly expressed in a number of types of cancer. In the present study, USP22 expression and its associations with Aurora-B and Survivin, and the clinicopathological features in OSCC were explored. USP22 is highly expressed in OSCC. Overexpression of USP22 is associated with lymph node metastasis and histological grade (P<0.01). Additionally, the expression of USP22 was positively associated with Aurora-B (P<0.01), Survivin (P<0.01), and Ki-67 (P<0.01). Furthermore, USP22 small interfering RNA inhibited cell growth and reduced the expression levels of Aurora-B, Survivin and Cyclin B, together with the upregulation of cyclin-dependent kinase inhibitor 1A (p21). These data suggest that USP22, Aurora-B and Survivin promote the OSCC development and may represent novel targets for OSCC diagnosis and treatment in the future.

Concentrations of VEGF and PlGF Decrease in Eyes After Intravitreal Conbercept Injection.

INTRODUCTION: Conbercept is a new anti-vascular endothelial growth factor drug approved for the treatment of age-related macular degeneration by the China Food and Drug Administration (CFDA) in 2013. In this study, we for the first time evaluated the concentrations of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) after patients with proliferative diabetic retinopathy were treated with intravitreal conbercept (IVC) injection. METHODS: Sixteen patients with proliferative diabetic retinopathy were randomly divided into two equal groups (A and B). Nine patients with rhegmatogenous retinal detachment were used as the control group. The patients in group A received 0.5 mg IVC and their aqueous humor was collected. After 7 days, all patients underwent vitrectomy, and their aqueous and vitreous humor were collected. RESULTS: In the aqueous humor, the concentrations of VEGF and PlGF were higher pre- than post-IVC injection in group A. Similarly, the concentrations of VEGF and PlGF in group A (pre-IVC) and group B were higher than those in the control group. In vitreous humor, the concentrations of VEGF and PlGF were higher in group B than those in the control group, and the concentrations of VEGF were lower in group A (post-IVC) than those in group B. CONCLUSIONS: Our study proved that the concentration of VEGF and PlGF reduced after IVC injection in aqueous humor. However, the concentration of PlGF did not reduce after IVC injection in vitreous humor.

Role of Vitamin A in the Immune System.

Vitamin A (VitA) is a micronutrient that is crucial for maintaining vision, promoting growth and development, and protecting epithelium and mucus integrity in the body. VitA is known as an anti-inflammation vitamin because of its critical role in enhancing immune function. VitA is involved in the development of the immune system and plays regulatory roles in cellular immune responses and humoral immune processes. VitA has demonstrated a therapeutic effect in the treatment of various infectious diseases. To better understand the relationship between nutrition and the immune system, the authors review recent literature about VitA in immunity research and briefly introduce the clinical application of VitA in the treatment of several infectious diseases.