Exploring the oncostatin M (OSM) feed-forward signaling of glioblastoma via STAT3 in pan-cancer analysis

Abstract

Background Oncostatin M (OSM) has been reported to be a key regulating factor in the process of tumor development. Previous studies have demonstrated both the promotion and inhibition effects of OSM in tumors, therefore inspiring controversies. However, no systematic assessment of OSM across various cancers is available, and the mechanisms behind OSM-related cancer progression remain to be elucidated. Methods Based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, we conducted a pan-cancer analysis on OSM to explore its tumor-related functions across cancers as well as its correlations with specific molecules, cells in the tumor microenvironment. Considering the results of pan-cancer analysis, we chose the specific tumor glioblastoma multiforme (GBM) to screen out the OSM-induced signaling pathways and intercellular communications in tumor progression. Wound scratch assay, invasion assay and qRT-PCR were performed to verify the biological effects of OSM on glioblastoma cells. Results Higher OSM level was found in most tumor tissues compared with corresponding normal tissues, and the enhanced OSM expression was observed to be strongly related to patients’ poor prognosis in several cancers. Moreover, the expression of OSM was associated with stromal and immune cell infiltration in the tumor microenvironment, and OSM-related immune checkpoint and chemokine co-expression were also observed. Our results suggested that OSM could communicate extensively with the tumor microenvironment. Taking GBM as an example, our study found that two critical signaling pathways in OSM-related tumor progression by KEGG enrichment analysis: Jak-STAT and NF-κB pathways. Single-cell RNA sequencing data analysis of GBM revealed that OSM was mainly secreted by microglia, and cell–cell interaction analysis proved that OSM-OSMR is an important pathway for OSM to stimulate malignant cells. In vitro, OSM treatment could facilitate the migration and invasion of glioblastoma cells, meanwhile promote the proneural-mesenchymal transition. The administration of STAT3 inhibitors effectively suppressed the OSM-mediated biological effects, which proved the key role of STAT3 in OSM signaling. Conclusion Taken together, our study provides a comprehensive understanding with regard to the tumor progression under the regulation of OSM. OSM seems to be closely related to chronic inflammation and tumor development in the tumor microenvironment. As an important inflammatory factor in the tumor microenvironment, OSM may serve as a potential immunotherapeutic target for cancer treatment, especially for GBM.

Genetic evolution and cellular interactions within the tumour microenvironment determine glioblastoma progression

“…No co-localisation patterns were observed in the classical subtype tumours. Association between microglia/macrophage OSM expression and induction of mesenchymal-like expression programs in glioma has been reported by previous studies and proposed to be induced via the upregulation of STAT3 signalling in neoplastic cells (Natesh et al, 2015;Junk et al, 2017;Hara et al, 2021;Chen et al, 2021). OSM is a cytokine belonging to the IL-6 family, which is secreted by macrophages and microglia in the brain to regulate inflammatory responses (Modur et al, 1997).…”

“…OSM is a cytokine belonging to the IL-6 family, which is secreted by macrophages and microglia in the brain to regulate inflammatory responses (Modur et al, 1997). There is contradictory evidence for the role of OSM in glioma progression with some studies suggesting it exhibits anti-tumorigenic effects (Friedrich et al, 2001), while others have reported pro-invasive properties and an overall negative association between OSM expression and glioma patient survival (Natesh et al, 2015, Chen et al, 2021. Beyond the influence of stromal cells in the microenvironment, Varn et al (2022) also observed that specific somatic alterations, such as NF1, EGFR or PDGFRA, are associated with mesenchymal transitions.…”

Prognostic and Immunological Role of STK38 across Cancers: Friend or Foe?

“…Furthermore, we found that STK38 plays a significant role in cancer immunity. The cancer immune status is discovered to be closely related to the infiltrating concentration and composition of the immune-related cells in the TME [ 28 , 29 , 30 ]. Past studies have demonstrated that STK38 is correlated with innate and adaptive immune responses.…”

Insights Into the Prognostic Value and Immunological Role of NAAA in Pan-Cancer

“…Another important finding of this study is that NAAA plays an essential role in cancer immunity. Over the past years, more and more studies have illustrated that the immune status of tumors closely depended on the composition and infiltrating concentration of cells in their corresponding environment (47)(48)(49). ESTIMATE algorithm was proven to be convenient and fast to predict tumor purity, which reflects the features of TME, and has proven to be a prognostic factor in human malignancies, especially in colon cancer patients (50).…”