Previous studies have shown that HOXB5 is involved in embryo development, immune cell differentiation, and vascular remodeling[23, 24]. Aberrant HOXB5 expression has been demonstrated to have carcinogenic effects and to promote the development of breast cancer and pancreatic cancer[25, 26]. However, the expression pattern of HOXB5 and its potential prognostic impact on glioma remains to be elucidated. In our study, high throughput RNA-seq data from TCGA and CGGA databases demonstrated that the HOXB5 expression was upregulated in glioma tissues and was associated with a series of clinicopathologic characteristics including WHO grade, histological type, and molecular type. Using stratified survival analysis, we established that a high HOXB5 expression represents an important unfavorable factor for the prognosis of glioma patients. Furthermore, multiple functional analyses indicated that angiogenesis, inflammatory response, and the IL6/JAK-STAT3 signaling pathway were significantly enriched in samples expressing high levels of HOXB5. Finally, our study showed that several microenvironment-infiltrated immune as well as stromal cells and immune checkpoint markers were significantly correlated with HOXB5 expression in glioma. These findings suggest that HOXB5 may serve as a potential indicator of malignancy and as a prognostic marker for glioma patients.
Under normal conditions, HOX genes regulate the vertebrate central nervous system development at specific time points. This pattern is called ‘spatial and temporal specificity’. An aberrant expression pattern is generally found in poorly differentiated samples and is associated with oncogenic effects. Our study showed that compared to that in normal brain tissues, the expression of HOXB5 was significantly higher in glioma tissues. Furthermore, overexpression of HOXB5 was significantly enriched in patients with aggressive features including WHO Grade IV, IDH-wildtype, unmethylated MGMT promoter, and GBM. Moreover, mesenchymal GBM, the most aggressive and least differentiated subtype of glioma, exhibited the highest HOXB5 levels amongst the subtypes. These findings demonstrate that glioma tissues with elevated expression of HOXB5 have malignant pathological phenotypes. In addition, the Kaplan-Meier survival analysis showed that high HOXB5 expression was highly relevant with unfavorable overall survival (OS) among glioma patients. The stratified univariate Cox regression analysis also indicated that HOXB5 expression remains a powerful forecaster of most of the glioma subgroup prognoses. We obtained similar results following the analysis of the validation datasets. Collectively, our analyses indicate that HOXB5 is an oncogenic gene and may serve as a promising biomarker for predicting the malignancy and prognosis.
Several studies have shown that both glioma purity and the infiltrated immune cell components have clinical and molecular implications[29, 30]. While lower purity represents aggressive progression, worse prognosis, and overloaded immune activity, the infiltration of immune cells is associated with the biological behavior and survival of glioma patients. We found that HOXB5 was significantly corelated with the immune score, stromal score, and glioma purity. This indicated that the tissue microenvironment with high HOXB5 expression has more variations and complexities. Consistently, positive correlations were discovered between HOXB5 and MDSCs as well as regulatory T cells. MDSCs can mediate tumor-induced immune tolerance and secrete IL-6. Simultaneously, Treg cells can suppress the effector T cell responses through a variety of mechanisms. High enrichment of MDSCs and Treg cells in glioma often indicates an immune suppressive microenvironment that promotes tumor progression and facilitates tumor immunity escape. These observations may explain why glioma patients overexpressing HOXB5 have aggressive phenotypes and devastating outcomes.
Immune checkpoint blockade is emerging as a promising strategy for neoplasm treatment. PD-1 as well as CTLA4, LAG3, and TIM3 have been investigated in a clinical setting as potential targets for cancer treatment. We identified significant correlations between HOXB5 and most of these targets. Therefore, it can be hypothesized that glioma patients with an increased expression of HOXB5 might benefit more from immune checkpoint blockade treatments.
Angiogenesis is one of the characteristics of malignant glioma, contributing to tumor proliferation and unfavorable prognosis. The activation of the inflammatory response and IL6/JAK-STAT3 signaling pathway has been shown to play important roles in promoting this process[35, 36]. In the present study, the multiple functional analysis of HOXB5-corelated genes revealed a significant association between HOXB5 and the regulation of angiogenesis, inflammatory response, and the IL6/JAK-STAT3 pathway. It is worth noting that Fessner et al. have reported that the overexpression of HOXB5 can enhance blood vessel remodeling as well as leucocyte infiltration in vivo by upregulating IL6. Consistently, the population of endothelial cells recruited by the glioma microenvironment was positively associated with HOXB5 expression (r = 0.24). Hence, based on these findings, we could conceivably hypothesize that HOXB5 might participate in the regulation of the inflammatory response and neovascularization. Considering the role of HOXB5 in the prognosis of glioma, it may serve as a promising potential target for developing new therapeutic strategies targeting the angiogenic process in glioma. However, further studies are required to better understand the underlying mechanisms of HOXB5 through which it regulates the glioma microenvironment.
Although our research improved our understanding on the relationship between HOXB5 and glioma, there were a few limitations worth mentioning. The current study was performed by using RNA-seq data from TCGA database; therefore, the HOXB5 mRNA expression levels should be verified using cell lines and clinical samples. Secondly, due to the limitations of public databases, several clinical factors, such as details regarding the treatments of the patients, remained uncovered. Furthermore, the study of the direct mechanisms of HOXB5 involved in the development of gliomas requires further functional experimental evaluation.