No abstract

The protein Dickkopf-1 (DKK1) is frequently overexpressed at the transcript level in hepatocellular carcinoma (HCC) and promotes metastatic progression through the induction of β-catenin, a Wnt signaling effector. We investigated how DKK1 expression is induced in HCC and found that activation of the epidermal growth factor receptor (EGFR) promoted parallel MEK-ERK and PI3K-Akt pathway signaling that converged to epigenetically stimulate DKK1 transcription. In HCC cell lines stimulated with EGF, EGFR-activated ERK phosphorylated the kinase PKM2 at Ser37, which promoted its nuclear translocation. Also in these cells, EGFR-activated Akt phosphorylated the acetyltransferase p300 at Ser1834. Subsequently, PKM2 and p300 mediated the phosphorylation and acetylation, respectively, of histone H3 at the DKK1 promoter, which synergistically enhanced DKK1 transcription. The mechanism was supported with mutational analyses in cells and in a chemically induced HCC model in rats. The findings suggest that dual inhibition of the MEK and PI3K pathways might suppress the expression of DKK1 and, consequently, tumor metastasis in patients with HCC.

Myocardial ischaemia (MI) remains a major cause of death and disability worldwide. Accumulating evidence suggests a significant role for innate immunity, in which the family of toll‐like receptors (TLRs) acts as an essential player. We previously reported and reviewed the changes of Tlr expression in models of MI. However, the underlying mechanisms regulating Tlr expression in MI remain unclear. The present study first screened transcription factors (TFs) that potentially regulate Tlr gene transcription based on in silico analyses followed by experimental verification, using both in vivo and in vitro models. Forkhead box C1 (FOXC1) was identified as a putative TF, which was highly responsive to MI. Next, by focusing on two representative TLR subtypes, an intracellular subtype TLR3 and a cell‐surface subtype TLR4, the regulation of FOXC1 on Tlr expression was investigated. The overexpression or knockdown of FoxC1 was observed to up‐ or down‐regulate Tlr3/4 mRNA and protein levels, respectively. A dual‐luciferase assay showed that FOXC1 trans‐activated Tlr3/4 promoter, and a ChIP assay showed direct binding of FOXC1 to Tlr3/4 promoter. Last, a functional study of FOXC1 was performed, which revealed the pro‐inflammatory effects of FOXC1 and its destructive effects on infarct size and heart function in a mouse model of MI. The present study for the first time identified FOXC1 as a novel regulator of Tlr expression and described its function in MI.

High expression of programmed death-ligand-1 (PD-L1) in hepatocellular carcinoma (HCC) cells usually inhibits the proliferation and functions of T cells, leading to immune suppression in tumor microenvironment. However, very little has been described regarding the mechanism of PD-L1 overexpression in HCC cells. In the present study, we found epidermal growth factor (EGF) stimulation promoted the expression of PD-L1 mRNA and protein in HCC cells. Inhibition of epidermal growth factor receptor (EGFR) could reverse EGF-induced the expression of PD-L1 mRNA and protein. Subsequently, we also observed that the phosphorylation level of Pyruvate kinase isoform M2 (PKM2) at Ser37 site was also increased in response to EGF stimulation. Expression of a phosphorylation-mimic PKM2 S37D mutant stimulated PD-L1 expression as well as H3-Thr11 phosphorylation in HCC cells, while inhibition of PKM2 significantly blocked EGF-induced PD-L1 expression and H3-Thr11 phosphorylation. Furthermore, mutation of Thr11 of histone H3 into alanine abrogated EGF-induced mRNA and protein expression of PD-L1, Chromatin immunoprecipitation (ChIP) assay also suggested that EGF treatment resulted in enhanced H3-Thr11 phosphorylation at the PD-L1 promoter. In a diethylnitrosamine (DEN)-induced rat model of HCC, we found that the expression of phosphorylated EGFR, PKM2 nuclear expression, H3-Thr11 phosphorylation as well as PD-L1 mRNA and protein was higher in the livers than that in normal rat livers. Taken together, our study suggested that PKM2-dependent histone H3-Thr11 phosphorylation was crucial for EGF-induced PD-L1 expression at transcriptional level in HCC. These findings may provide an alternative target for the treatment of hepatocellular carcinoma.

ObjectiveBreast cancer visceral crisis (VC) is caused by excessive tumor burden leading to severe organ dysfunction with poor prognosis. Traditional chemotherapy reduces the quality of life of patients without significantly improving survival. The aim of this study was to investigate the clinical characteristics of patients with VC and the prognosis by using different treatment options.MethodsAccording to the 5th European School of Oncology (ESO)–European Society for Medical Oncology (ESMO) international consensus guidelines for advanced breast cancer guidelines (ABC 5), patients who were treated in the First Hospital of Jilin University from 2018 to 2022 and diagnosed with breast cancer VC were retrospectively analyzed. The analysis focused on the characteristics of the patients, the treatment regimens, and prognosis.ResultsA total of 133 patients were included in this study. As for metastasis breast cancer subtype, 92 (69.18%) were hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER-2) negative, 20 (15.04%) had HER-2 overexpression, and 21 (15.78%) were triple negative. All patients had an mOS of 11.2 months (range, 1.1–107.8 months). In different types of VC, the median overall survival (mOS) of bone marrow metastasis (BMM) was 18.0 months (range, 2.0–107.8 months), that of diffuse liver metastasis (DLM) was 8.1 months (range, 1.3–30.2 months), and that of meningeal metastasis (MM) was 9.0 months (range, 1.2–53.8 months). In 92 HR+, Her-2− patients using different treatment regimens, mOS was 6.2 months (range, 1.2–29.8 months) in the chemotherapy group while it was 24.3 months (range, 3.1–107.8 months) in the endocrine therapy (ET) group. Multivariate Cox regression analysis suggested that Eastern Cooperative Oncology Group (ECOG) scores and type of VC were associated with survival.ConclusionPrognosis varied in different types of VC. Patients with BMM had the best prognosis, and DLM had the worst. As treatment options continue to progress, our retrospective study showed a significant prolongation of overall survival (OS) in patients with VC compared to previous studies.

High‐mobility group protein A2 (HMGA2) is highly expressed in hepatocellular carcinoma (HCC) cells and contributes to tumor metastasis and poor patient survival. However, the molecular mechanism through which HMGA2 is transcriptionally regulated in HCC cells remains largely unclear. Here, we showed that the expression HMGA2 was upregulated in HCC, and that elevated HMGA2 could promote tumor metastasis. Incubation of HCC cells with epidermal growth factor (EGF) could promote the expression of HMGA2 mRNA and protein. Mechanistic studies suggested that EGF can phosphorylate p300 at Ser1834 residue through the PI3K/Akt signaling pathway in HCC cells. Knockdown of p300 can reverse EGF‐induced HMGA2 expression and histone H3‐K9 acetylation, whereas a phosphorylation‐mimic p300 S1834D mutant can stimulate HMGA2 expression as well as H3‐K9 acetylation in HCC cells. Furthermore, we identified that p300‐mediated H3‐K9 acetylation participates in EGF‐induced HMGA2 expression in HCC. In addition, the levels of H3‐K9 acetylation positively correlated with the expression levels of HMGA2 in a chemically induced HCC model in rats and human HCC specimens.

Eucommia ulmoides Oliv. is a traditional medical plant in Asia; however, it is still unknown whether Eucommia male flowers have an antihypertensive activity. In this study, we found that the aqueous extract of Eucommia ulmoides Oliv. male flowers can lower the blood pressure of SHR in a dose-dependent manner. Mechanistic studies suggested that the aqueous extract of male flowers can promote the mRNA and protein expressions of ACE2 in the kidney of SHR. ELISA assay showed that the plasma levels of ANG II was decreased, while ANG-(1–7) was increased in SHR treated with the aqueous extract of male flowers. ACE2 inhibitor DX600 can reverse the aqueous extract of Eucommia ulmoides Oliv. male flower-induced downregulation of Ang II and upregulation of Ang-(1–7), as well as the reduction of blood pressure in SHR. Moreover, Ang-(1–7)-Mas receptor antagonist A-779 abolished the antihypertensive effects of the aqueous extract of Eucommia ulmoides Oliv. male flower in SHR. The aqueous extract of Eucommia ulmoides Oliv. male flowers exhibited an antihypertensive action through the activation of ACE2-Ang-(1–7)-Mas signaling pathways in spontaneously hypertensive rats.

Intervertebral disc degeneration (IVDD) is a main cause of lower back pain, leading to psychological and economic burdens to patients. Physical therapy only delays pain in patients but cannot eliminate the cause of IVDD. Surgery is required when the patient cannot tolerate pain or has severe neurological symptoms. Although surgical resection of IVD or decompression of the laminae eliminates the diseased segment, it damages adjacent normal IVD. There is also a risk of re-protrusion after IVD removal. Cell therapy has played a crucial role in the development of regenerative medicine. Cell transplantation promotes regeneration of degenerative tissue. However, owing to the lack of vascular structure in IVD, sufficient nutrients cannot be provided for transplanted mesenchymal stem cells (MSCs). In addition, dead cells release harmful substances that aggravate IVDD. Extracellular vesicles (EVs) have been extensively studied as an emerging therapeutic approach. EVs generated by paracrine MSCs retain the potential of MSCs and serve as carriers to deliver their contents to target cells to regulate target cell activity. Owing to their double-layered membrane structure, EVs have a low immunogenicity and no immune rejection. Therefore, EVs are considered an emerging therapeutic modality in IVDD. However, they are limited by mass production and low loading rates. In this review, the structure of IVD and advantages of EVs are introduced, and the application of MSC-EVs in IVDD is discussed. The current limitations of EVs and future applications are described.