The IL-6R/JAK2/STAT3 pathway mediated by interleukin-6 (IL-6) plays an important role in the occurrence and development of multiple myeloma (MM), which is associated with decreased microRNA-451a. However, the biological function of microRNA-451a in MM remains unclear. The bone marrow (BM) of patients with MM was sampled, and the plasma cells were enriched. BM miR-451a, IL-6 and IL-6R levels and Ki-67 expression intensity were evaluated using reverse transcription-quantitative PCR, ELISA and flow cytometry, respectively. U266 cell proliferation, viability and apoptosis were measured using BrdU, CCK-8 and Annexin V/propidium iodide assays, respectively. Total and phospo-(p-)JAK2 and p-STAT3 levels were measured by western blotting. Dual-luciferase reporter assays were performed to validate the predicted target binding sites. miR-451a expression was low in patients with MM and was associated with the Revised International Staging System (R-ISS) stage. IL-6 concentrations were significantly higher in patients with MM than in normal controls and were inversely associated with miR-451a levels (r=-0.96, P<0.0001). IL-6R levels were positively correlated with the R-ISS stage. miR-451a was downregulated, and IL-6R was upregulated in myeloma cell lines. Treatment with an miR-451a mimic inhibited viability and induced apoptosis in U266 cells. p-JAK2 and p-STAT3 levels were significantly lower in mimic-treated U266 cells than in control cells. Thus, miR-451a was shown to regulate myeloma cell proliferation and apoptosis via the IL-6R/JAK2/STAT3 pathway and may be used to predict patient prognosis.
The natural course of multiple myeloma (MM) varies greatly between patients. The Revised MM International Staging System (R‑ISS) identifies high‑risk patients, but it is unsuitable for assessing minimal residual disease (MRD). Furthermore, the focal location of myeloma cells and clonal evolution often produce false negative results in flow cytometry. Extracellular microRNA (miRNA/miR) expression levels are stable in bodily fluids, and are retrievable and measurable from fresh or archived serum or plasma samples. Therefore, the present study aimed to investigate the clinical utility of circulating miRNA levels in patients with MM, particularly miR‑451a, which is commonly downregulated in MM, and whether it could predict the prognosis and relapse of patients with MM. In total, 66 patients with MM, stratified using the R‑ISS criteria, were recruited, while 10 healthy subjects (transplantation donors) were enrolled as controls. Reverse transcription‑quantitative PCR was used to evaluate miR‑451a expression in bone marrow (BM) and in the circulation. IL‑6 levels were measured using ELISA, while western blotting was conducted to analyze the protein expression levels of the IL‑6 receptor (IL‑6R). During follow‑up, MRD was assessed via multiparameter flow cytometry (MFC). miR‑451a was identified to target IL‑6R using a dual‑luciferase reporter assay. Circulating miR‑451a levels were low in patients with MM, and was found to be 0.39 times that of the control group (U=4.00; P<0.001). Among the 66 patients with MM, the median level of miR‑451a was 0.73 and 0.41 times that of the control group in R‑ISS stage I MM (15 patients) and R‑ISS stage II stage (17 patients), respectively; patients with R‑ISS stage III MM (34 patients) had the lowest level, at 0.24 times the value of the control group. Circulating miR‑451a levels had a strong positive correlation with miR‑451a levels in BM, but negatively correlated with IL‑6 and IL‑6R levels. After two courses of consolidation chemotherapy, 19 patients achieved complete remission, 10 of whom presented steady circulating miR‑451a levels during follow‑up; the other nine patients had an abrupt decrease in circulating miR‑451a levels. The turning points in the trend appeared 4‑8 weeks before positive results were obtained via MFC, and 4‑16 weeks before clinical relapse. Moreover, miR‑451a overexpression notably downregulated the expression of the IL‑6R mRNA and protein. Collectively, circulating miR‑451a levels potentially represent a novel biomarker to monitor MRD and predict relapse.
We, for the first time, prove a compact version of $T1$ theorem for singular integrals of Zygmund type on $\mathbb{R}^3$. That is, if a singular integral operator $T$ associated with Zygmund dilations admits the compact full and partial kernel representations, and satisfies the weak compactness property and the cancellation condition, then $T$ can be extended to a compact operator on $L^p(\mathbb{R}^3)$ for all $p \in (1, \infty)$. Let $\theta \in (0, 1]$ be the kernel parameter, and let $A_{p, \mathcal{R}}$ and $A_{p, \mathcal{Z}}$ respectively denote the class of of strong $A_p$ weights and the class of $A_p$ weights adapted to Zygmund dilations. Under the same assumptions as above, we establish more general results: if $\theta \in (0, 1)$, $T$ is compact on $L^p(w)$ for all $p \in (1, \infty)$ and $w \in A_{p, \mathcal{R}}$; if $\theta=1$, $T$ is compact on $L^p(w)$ for all $p \in (1, \infty)$ and $w \in A_{p, \mathcal{Z}}$.
To observe the effect of protein kinase D1 (PKD1) on the growth and metabolism of oral squamous cell carcinoma HSC-4 cells and related molecular mechanisms in the tumor microenvironment.HSC-4 cell lines were transfected with shRNA plasmids. Three groups (Wild, control-shRNA, and PKD1-shRNA) were cultured under acidic or hypoxic environment for a certain time. Western blot was used to detect the expression of autophagy-related and glycolytic-related proteins. The proliferation changes were detected by CCK-8 kits.The PKD1-knockdown HSC-4 cell line was established. PKD1 silencing increased autophagy activity. Under hypoxic and acidic conditions, the PKD1-knockdown HSC-4 cells showed lower proliferation than the parental cells. PKD1-knockdown also decreased the expression of hypoxia induciblefactor 1α (HIF-1α) and pyruvate kinase M2 (PKM2).Under hypoxic and acidic conditions, PKD1 gene silencing can increase apoptotic autophagy activity. Downregulated PKD1 gene expression can reduce the glycolysis of oral squamous cell carcinoma cells and inhibit tumor cell proliferation. This study revealed the important role of PKD1 in the metabolism and growth of oral squamous cell carcinoma, making it a possible target for the treatment of oral squamous cell carcinoma.目的 探讨在酸性缺氧微环境中，蛋白激酶D1（PKD1）对口腔鳞癌HSC-4细胞生长、代谢的调控作用和相关分子机制。方法 口腔鳞癌HSC-4细胞稳定转染PKD1，将未转染组、对照组和转染组细胞分别置于酸性或缺氧环境下进行培养，Western blot检测细胞中PKD1敲除率及细胞自噬相关蛋白和糖酵解相关蛋白表达情况，CCK8试剂盒检测细胞增殖。结果 实验成功建立了PKD1基因沉默的稳定细胞株；酸性环境下，PKD1沉默后细胞自噬活性升高；缺氧环境下，相对于对照组，PKD1基因沉默后细胞缺氧诱导因子1α（HIF-1α）和糖酵解中丙酮酸激酶（PKM2）的表达均显著降低；酸性和缺氧环境下，相对于对照组，PKD1基因沉默后细胞的生长速度显著降低。结论 在酸性和缺氧环境下，PKD1基因沉默可促使口腔鳞癌细胞凋亡性自噬活性升高，且下调PKD1基因表达可抑制口腔鳞癌细胞糖酵解，进而抑制肿瘤细胞增殖。揭示PKD1在口腔鳞癌代谢和生长中的作用，使其成为口腔鳞癌治疗的可能靶点。.
Cancer is known as one of the leading causes of death in the world with difficult diagnose at early stages, poor prognosis and high mortality. Animal-based experiments and clinical trials have always been the main approach for cancer research, albeit they may have limitations and ethical issues. Mathematicalmodeling as an efficient method is used to predict results, optimize experimental design and reduce animal use. Our work focuses on the phenomenological simulation of cancer progression and therapies at the cell scale level.
Abstract Multiple myeloma (MM) is an incurable hematological malignancy characterized by abnormal infiltration of plasma cells in the bone marrow. MicroRNAs (miRNAs) have emerged as crucial regulators in human tumorigenesis and tumor progression. miR-27, a novel cancer-related miRNA, has been confirmed to be implicated in multiple types of human tumors; however, its biological role in MM remains largely unknown. The present study aimed to characterize the biological role of miR-27 in MM and elucidate the potential molecular mechanisms. Here we found that miR-27 was significantly up-regulated in MM samples compared with normal bone marrow samples from healthy donors. Moreover, the log-rank test and Kaplan–Meier survival analysis displayed that MM patients with high miR-27 expression experienced a significantly shorter overall survival than those with low miR-27 expression. In the current study, we transfected MM cells with miR-27 mimics or miR-27 inhibitor to manipulate its expression. Functional studies demonstrated that miR-27 overexpression promoted MM cell proliferation, facilitated cell cycle progression, and expedited cell migration and invasion; whereas miR-27 knockdown inhibited cell proliferation, induced cell cycle arrest, and slowed down cell motility. Mechanistic studies revealed that Sprouty homolog 2 (SPRY2) was a direct target of miR-27 and that rescuing SPRY2 expression reversed the promoting effects of miR-27 on MM cell proliferation, migration, and invasion. Besides, miR-27 ablation suppressed tumorigenecity of MM cells in mouse xenograft models. Collectively, our data indicate that miR-27 exerts its oncogenic functions in MM by targetting SPRY2 and that miR-27 may be used as a promising candidate target in MM treatment.
Cell migration, known as an orchestrated movement of cells, is crucially important for wound healing, tumor growth, immune response as well as other biomedical processes. This paper presents a cell-based model to describe cell migration in non-isotropic fibrin networks around pancreatic tumor islets. This migration is determined by the mechanical strain energy density as well as cytokines-driven chemotaxis. Cell displacement is modeled by solving a large system of ordinary stochastic differential equations where the stochastic parts result from random walk. The stochastic differential equations are solved by the use of the classical Euler–Maruyama method. In this paper, the influence of anisotropic stromal extracellular matrix in pancreatic tumor islets on T-lymphocytes migration in different immune systems is investigated. As a result, tumor peripheral stromal extracellular matrix impedes the immune response of T-lymphocytes through changing direction of their migration.
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