Upregulation of SPP1 Is a Marker for Poor Lung Cancer Prognosis and Contributes to Cancer Progression and Cisplatin Resistance

Abstract

The chemoresistance of lung cancer is a significant contributor to its high mortality and morbidity rate. There is an urgent need to identify differentially expressed genes in lung cancer patients with a poor prognosis to develop effective means to overcome drug resistance in subsequent treatment. In this study, we identified the secreted phosphoprotein 1 (SPP1) as a potential gene associated with a poor diagnosis of lung cancer patients using the Cancer Genome Atlas analysis, which suggested that the expression of SPP1 in tumor tissues was significantly higher than normal tissues. The high expression of SPP1 was also correlated with tumor grade and poor clinical prognosis. To understand the roles of SPP1 and the DNA methyltransferase 1 (DNMT1), which regulated SPP1 expression, in affecting cell viability, migration and invasion, SPP1 and DNMT1 were overexpressed in the human lung cancer A549 and NCI-446 cells, followed by analyzing cell viability, migration and invasion. We showed that SPP1 promoted the proliferation, migration and invasion of lung cancer cells, and increased the resistance of lung cancer to the chemotherapeutic drug cisplatin. Knocking down SPP1 in cells restored sensitivity to cisplatin. Further, A549 cells without SPP1 overexpression demonstrated lower tumor growth rate than SPP1 overexpression cells using the xenograft tumor mouse model. High expression of SPP1 in lung cancer tumor tissue was caused by the reduced methylation level of its promoter region mediated by DNMT1. Our data suggested that SPP1 can be used as a marker for highly malignant lung cancer and targeting SPP1 may be a potential lung cancer treatment strategy.

An Integrated Bioinformatics Analysis towards the Identification of Diagnostic, Prognostic, and Predictive Key Biomarkers for Urinary Bladder Cancer

“…Significantly, expression of SPP1 showed a subtypedependent effect on chemotherapy response [75], which was also confirmed in our analysis. More specifically, we found that patients who had higher SPP1 expression levels showed a lower response to cisplatin-based chemotherapy, which is also supported by previous evidence from the literature and research on other types of cancers, such as lung [181] and ovarian cancer [182]. Results from another study found that SPP1 was upregulated in upper tract urothelial carcinoma cells and tissues, and high plasma SPP1 expression levels were strongly connected with higher stage and grade [183].…”

Single‐cell RNA‐seq dissecting heterogeneity of tumor cells and comprehensive dynamics in tumor microenvironment during lymph nodes metastasis in gastric cancer

“…When comparing intercellular networks between PT and MLN, the activation of SPP1 signaling pathway was detected in MLN instead of PT (Figure 6B,C and Supplementary Figure 9). A high expression of SPP1 indicated a poor prognosis in lung adenocarcinoma, hepatocellular carcinoma, cervical cancer, and other cancer types 25,26 . The further validation in TCGA database confirmed that patients expressed high level of SPP1 showed poor overall survival (Figure 6D).…”

Construction of immune related prognostic model for pancreatic ductal adenocarcinoma based on single cell RNA-seq analysis

“…SPP1 gene is located in 4q22.1, and encodes the secreted phosphoprotein 1, which is involved in cell adhesion to the extracellular matrix (ECM) [38,39], tumor proliferation, migration [40], chemoresistance [41], and macrophage polarization [30][31]. SPP1 was a promising biomarker for tumor diagnosis and prognosis [23,42,43]. However, the expression and distribution of SPP1 in the different cell subpopulations of PDAC tissue are poorly understood.…”