Integrating the tumor-suppressive activity of Maspin with p53 in retuning the epithelial homeostasis: A working hypothesis and applicable prospects

Abstract

Epithelial malignant transformation and tumorous development were believed to be closely associated with the loss of its microenvironment integrity and homeostasis. The tumor-suppressive molecules Maspin and p53 were demonstrated to play a crucial role in body epithelial and immune homeostasis. Downregulation of Maspin and mutation of p53 were frequently associated with malignant transformation and poor prognosis in various human cancers. In this review, we focused on summarizing the progress of the molecular network of Maspin in studying epithelial tumorous development and its response to clinic treatment and try to clarify the underlying antitumor mechanism. Notably, Maspin expression was reported to be transcriptionally activated by p53, and the transcriptional activity of p53 was demonstrated to be enhanced by its acetylation through inhibition of HDAC1. As an endogenous inhibitor of HDAC1, Maspin possibly potentiates the transcriptional activity of p53 by acetylating the p53 protein. Hereby, it could form a “self-propelling” antitumor mechanism. Thus, we summarized that, upon stimulation of cellular stress and by integrating with p53, the aroused Maspin played the epigenetic surveillant role to prevent the epithelial digressional process and retune the epithelial homeostasis, which is involved in activating host immune surveillance, regulating the inflammatory factors, and fine-tuning its associated cell signaling pathways. Consequentially, in a normal physiological condition, activation of the above “self-propelling” antitumor mechanism of Maspin and p53 could reduce cellular stress (e.g., chronic infection/inflammation, oxidative stress, transformation) effectively and achieve cancer prevention. Meanwhile, designing a strategy of mimicking Maspin’s epigenetic regulation activity with integrating p53 tumor-suppressive activity could enhance the chemotherapy efficacy theoretically in a pathological condition of cancer.

Correlation between Maspin Levels in Different Biological Samples and Pathologic Features in Colorectal Adenocarcinomas

“…It was recently established that maspin is epigenetically regulated at the tissue level with variations depending on each histological type [9][10][11][12]. Epigenetic changes in maspin expression involve: cytosine (de)methylation; deacetylation of histones; decreased chromatin accessibility, causing loss of gene function.…”

“…Maspin gene promoter methylation is involved in several cancers such as breast, thyroid, skin, and colon cancers and it was admitted that this is one of the most common mechanisms that causes loss of gene function. It is noteworthy that in somatic tissues, most CpG regions are methylated and tumor cells show global hypomethylation of DNA compared to their normal counterparts [9][10][11][12]. Hypomethylation is involved in the progression from premalignant to malignant and leads to the activation of genes involved in the development of cancer [9][10][11][12].…”

“…It is noteworthy that in somatic tissues, most CpG regions are methylated and tumor cells show global hypomethylation of DNA compared to their normal counterparts [9][10][11][12]. Hypomethylation is involved in the progression from premalignant to malignant and leads to the activation of genes involved in the development of cancer [9][10][11][12].…”

“…The secreted maspin binds to the components of the extracellular matrix. A plausible hypothesis is that maspin exerts its role only in the nucleus at the level of gene or chromatin regulation and in this way, it indirectly affects the interaction between the cell and the matrix, being released as a consequence of cell damage/necrosis [9][10][11][12].…”

Minimally Invasive and Fast Diagnosis of Gastric Cancer Based on Maspin Levels in Different Biological Samples

“…Deng et al [1,7] demonstrated that the down-regulated expression of maspin and the up-regulated expression of uPA and MMP-7 play important roles in the invasion and metastasis of gastric carcinoma; accordingly, they can serve as biomarkers for the biopathological behavior of gastric tumors. Overall, maspin has proved to have a significative role in cancer diagnosis and prognosis [1,[8][9][10][11][12]. The expression of maspin was also used for the determination of the efficiency of treatment of gastric cancer, e.g., using fluorouracil-based chemotherapy [13].…”