Ski Regulates the Inflammatory Response of Reactive Astrocytes Induced by Oxygen Glucose Deprivation/Reoxygenation (OGD/R) Through the NF-κB Pathway.

Spinal cord injury (SCI) is a common disease of the nervous system, including primary and secondary injuries. Neuronal inflammation after SCI is the most important pathological process of SCI and a chemical barrier to nerve function recovery after injury. Ski, an evolutionarily conserved functional transcriptional regulator protein, is upregulated in reactive astrocytes after SCI and regulates the biological characteristics of astrocytes. However, its role in the glial inflammatory response triggered by reactive astrocytes after spinal cord ischemia and its exact mechanism remains unclear. This study investigated the role and mechanism of Ski in the inflammatory response triggered by reactive astrocytes induced by oxygen and sugar deprivation/reoxygenation (OGD/R) model in vitro. In the ODG/R model, Ski expression was upregulated. In contrast, Ski upregulation was accompanied by increased levels of iNOS, IL-1ß, IL-6, TNF-α, and other inflammation-related factors. These results indicated that the inflammatory response triggered by astrocytes was significantly enhanced in OGD/R-stimulated astrocytes. Astrocytes were transfected with Ski specific siRNA to knock out Ski and subsequently attenuate OGD-induced astrocyte-triggered inflammation. Our results also suggest that Ski downregulation downregulates the expression of iNOS, IL-1ß, IL-6, and TNF-α in OGD/R-induced reactive astrocytes by inhibiting the activity of the NF-κB signaling pathway. In conclusion, downregulation of Ski can effectively inhibit glial inflammation in SCI by inhibiting the activity of the NF-κB pathway. These findings suggest that Ski is a promising therapeutic target for inflammatory responses after SCI.In conclusion, Ski downregulation can effectively inhibit glial inflammation in SCI by inhibiting the activity of the NF-κB pathway. These findings suggest that Ski might serve as a promising target for the treatment of inflammatory responses after SCI.

Ski regulates proliferation and migration of reactive astrocytes induced by lipopolysaccharide (LPS) through PI3K/Akt pathway.

Spinal cord injury (SCI) is a leading cause of disability and death worldwide. Reactive astrogliosis, a typical feature of SCI, undergoes various molecular and morphological changes and contributes to glial scar formation, which impedes axonal regeneration. Ski is a novel molecule that regulates the biological characteristics of astrocytes after spinal cord injury, but its function and the exact mechanism of its overexpression in reactive astrocyte proliferation and migration after SCI remain unclear. The purpose of this study was to elucidate the effect and mechanism of Ski on the proliferation and migration of reactive astrocytes, and to regulate the spatiotemporal formation of glial scars after SCI. In an in vitro lipopolysaccharide (LPS)-induced astrocyte injury model, the expression of Ski was upregulated in a time-dependent manner in LPS-induced astrocytes, and the upregulation of Ski was accompanied by that of PCNA, CDK4, CyclinD1, and other proliferation-related proteins. Our findings suggest that Ski promotes the proliferation and migration of reactive astrocytes. Next, astrocytes were transfected with a specific lentivirus to cause the overexpression of Ski, which significantly enhanced the proliferation and migration of reactive astrocytes and LPS-induced activation of the PI3K/Akt pathway. The PI3K/Akt pathway inhibitor LY294002 significantly inhibited the proliferation and migration of LPS-induced reactive astrocytes after Ski overexpression. In conclusion, Ski regulates LPS-induced astrocyte proliferation and migration through the PI3K/Akt pathway, making Ski a promising target for strategies to combat glial scarring after SCI.

Transcription Factor SP2 Regulates Ski-mediated Astrocyte Proliferation In Vitro.

Transcription factors bind specific sequences upstream of the 5' end of their target genes to ensure proper spatiotemporal expression of the target gene. This study aims to demonstrate that the transcription factor SP2 regulates expression of the Ski gene, which has specific binding sites for SP2, and thus enables Ski to regulate astrocyte proliferation. The upstream regulation mechanism of astrocyte proliferation was explored to further regulate the formation of glial scar in specific time and space after spinal cord injury. JASPAR and UCSC databases were used to predict transcription factor binding and the threshold was gradually reduced to screen transcription factors upstream of Ski, leading to the identification of SP2. Next, we analyzed the correlation between the expression of SP2 and Ski in normal astrocytes and reactive astrocytes, as well as the changes in astrocyte proliferation. To confirm that SP2 regulates Ski during astrocyte proliferation, astrocytes were transfected siRNA targeting SP2 and then astrocyte proliferation were analyzed. Finally, a dual luciferase reporter assay and Chromatin immunoprecipitation (ChIP) assay confirmed that the promoter region of Ski contained a specific SP2 binding site. This is the first that SP2 has been identified and confirmed to play an important role in astrocyte proliferation by regulating Ski expression. These results may help identify novel targets for the treatment of spinal cord injury.

Roles of matrix metalloproteinase-7 (MMP-7) in cancer.

Matrix metalloproteinase-7 (MMP-7) is a small proteolytic enzyme that secretes zinc and calcium endopeptidases. It can degrade a variety of extracellular matrix substrates and other substrates and plays important regulatory roles in many human pathophysiological processes. Since its discovery, MMP-7 has been recognized as a regulatory protein in wound healing, bone growth, and remodeling. Later, MMP-7 was reported to regulate the occurrence and development of cancers and mediate the proliferation, differentiation, metastasis, and invasion of several types of cancer cells via various mechanisms. Thus, matrix metalloproteinase-7 may be a promising tumor biomarker and therapeutic target. The expression of MMP-7 correlates with the clinical characteristics of cancer patients, and its expression profile is a new diagnostic and prognostic biomarker for a variety of human diseases. Hence, manipulating the expression or function of MMP-7 may be a potential treatment strategy for different diseases including cancers. This review summarizes the role played by MMP-7 in carcinogenesis of several human cancers, underlying mechanisms, and its clinical significance of the occurrence and development of cancers.

Ski: Double roles in cancers.

The Ski (Sloan-Kettering Institute) is an evolutionarily conserved protein that plays a dual role as an oncoprotein and tumor suppressor gene in the development of human cancer. The Ski oncogene was first identified as a transforming protein of the avian Sloan-Kettering retrovirus in 1986. Since its discovery, Ski has been identified as a carcinogenic regulator in a variety of malignant tumors. Later, it was reported that Ski regulates the occurrence and development of some cancers by acting as an oncogene. Ski mediates the proliferation, differentiation, metastasis, and invasion of numerous cancer cells through various mechanisms. Several studies have shown that Ski expression is correlated with the clinical characteristics of cancer patients and is a promising biomarker and therapeutic target for cancer. In this review, we summarize the mechanisms and potential clinical implications of Ski in dimorphism, cancer occurrence, and progression in various types of cancer.

Role of HAND2-AS1 in human tumors.

Long noncoding RNAs (lncRNAs) are molecules more than 200 nucleotides in length. They play roles in various cells, mainly regulating cell growth, differentiation, and apoptosis. They also participate in the pathogenesis of many diseases. In fact, several studies have shown that lncRNAs function as cancer or tumor suppressor genes and play important roles in the occurrence and development of cancer in humans. New evidence has shown that lncRNA heart and neural crest derivatives expressed 2-antisense RNA 1 (lncRNA HAND2-AS1) hinders the occurrence and development of various tumors. Overexpression of HAND2-AS1 was found to be significantly related to the clinical and pathological characteristics of cancer patients, as well as the regulation of cell proliferation, apoptosis, invasion, metastasis, and energy metabolism through several possible mechanisms. Therefore, HAND2-AS1 may be a promising tumor biomarker and therapeutic target. Here, we review the biological functions, mechanisms, and potential clinical significance of HAND2-AS1 in numerous human tumors.

The role of long non-coding RNA MIAT in cancers.

Long non-coding RNAs (lncRNAs), a kind of non-coding single-strand RNAs, play an important role as carcinogenic genes or tumor suppressors in the development of human cancer. Myocardial infarction-associated transcript (MIAT) was first identified as a lncRNA in 2006 and originally isolated as a candidate gene for myocardial infarction. Later, it was reported that MIAT exhibits regulatory effects on the human cell cycle. Since its discovery, MIAT has also been identified as a carcinogenic regulator in many malignant tumors. High expression of MIAT is related to the clinicopathological characteristics of cancer patients. It can also regulate cell proliferation, invasion, metastasis, and anti-apoptosis through a variety of mechanisms. Therefore, MIAT is considered a potential biomarker and therapeutic target in cancer. In this review, we summarize the biological function, mechanism, and potential clinical significance of MIAT during tumorigenesis.