HSPD1, a protein originally nuclear but predominantly localized in mitochondria, exhibits a strong affinity for the auxiliary chaperone HSP10 through an ATP-mediated binding process. It plays a critical role in importing and folding proteins into mitochondria, crucial for cellular function and immune activation [10, 29]. In our study, we utilized the TCGA database to analyze HSPD1 expression across various cancers and found it significantly upregulated in tumor tissues compared to normal tissues. ROC curve analysis suggested HSPD1 could serve as a diagnostic marker. Data from the HPA indicated high HSPD1 protein expression in OSCC tissues and low expression in normal tissues. The correlation between elevated HSPD1 expression and poor clinical outcomes in HNSCC underscores its potential as a prognostic biomarker. Patients with higher levels of HSPD1 mRNA or protein expression exhibited poorer prognosis, correlating with advanced clinical stage, high histological grade, lymphovascular infiltration, and smoking.The findings of this study strongly indicate that elevated expression of HSPD1 plays a significant role in the pathogenesis and progression of Head and Neck Squamous Cell Carcinoma (HNSCC). Overexpression of this protein potentially acts as a critical factor in the molecular mechanisms underlying the proliferation and malignancy of HNSCC. A substantial body of evidence supports an oncogenic and prognostic role for HSPD1 across various cancer types. For instance, Aluksanasuwan et al. demonstrated that HSPD1 is involved in secretome alteration and induction of cancer-associated fibroblasts in lung cancer cells[30]. Moreover, emerging evidence links cytoplasmic HSPD1 to the survival and metastasis of diverse cancers [31, 32].
To explore the potential role of HSPD1 in HNSCC, we systematically examined differentially expressed genes (DEGs) categorized by HSPD1 expression levels. Among the upregulated DEGs, MYH7 is associated with hypertrophic obstructive cardiomyopathy, and mutations in the MYH7 gene are linked to various myocardial diseases[33]. PAK5 is implicated in the development of multiple tumors; it enhances n-calmodulin trans-activation to promote metastasis in renal cell carcinoma[34] and contributes to cervical cancer progression through modifications[35]. Low expression of MYL2 predicts poor prognosis in Rhabdomyosarcoma (RMS) and is a potential therapeutic target for reducing RMS mortality[36]. Among the downregulated DEGs, VIL1 involvement in HpSlyD mediated by TCTP proteins may be associated with gastrointestinal chemotaxis[37].FLG2 participates in acute cerebral ischemia-reperfusion injury and can serve as a biomarker for this condition[38]. Mutations in the DSG1 gene contribute to the development of palmoplantar striated keratosis[39]. According to GO analysis, HSPD1 impacts proteasomal protein catabolic processes and regulates protein transport, which are associated with pro-inflammatory responses and protein degradation[10]. KEGG analysis revealed HSPD1's involvement in the MAPK signaling pathway, a classical pathway in tumor biology[40]. The MAPK signaling cascade, involving ERK1/2, JNK1/2/3, and p38 modules, plays a crucial role in cell differentiation, proliferation, and metabolic regulation, maintaining cellular homeostasis and normal tissue function[41]. Studies consistently demonstrate that HSPD1 plays a multifunctional role in cancer progression, influencing various biological pathways critical for cancer development. This broad impact suggests that HSPD1's regulatory effects on these pathways are pivotal in shaping cancer pathogenesis and progression.
To identify potential pathways regulated by HSPD1, we conducted Gene Set Enrichment Analysis (GSEA). The results indicate that HSPD1 may impact HNSCC progression through the metabolism of xenobiotics by cytochrome P450 (CYP). The CYP superfamily comprises more than 50 heme-containing enzymes critical for maintaining physiological homeostasis. These enzymes facilitate the biosynthesis of lipids, cholesterol, and steroids, exerting broad systemic influence across various physiological processes[42]. Cytochrome P450 enzymes are integral to metabolic reactions involving drugs, steroids, and carcinogens[43–45], accounting for approximately 95% of organic chemical oxidation/reduction reactions[46]. Aberrant expression and function of CYPases are implicated in cancers such as lung, colon, pancreatic, and adrenal cancers[47–50]. Specific CYP enzymes like 17A1 and 21A2 play crucial roles in genetic defects leading to various endocrine diseases[51]. Studies by Duan Y et al. have shown that down-regulating HSPD1 expression significantly promotes proliferation and migration in ovarian cancer cells. The mechanism involves HSPD1 deficiency destabilizing mitochondrial 3-oxolipoyl coenzyme A synthase (OXSM), thereby impacting cellular metabolism and signal transduction pathways[52]. Consistently,our study demonstrated that HSPD1 knockdown reduces cell proliferation and migration, aligning with previous findings[53].Future research could explore HSPD1's roles in regulating cell cycle dynamics and apoptosis pathways to further elucidate its broader biological impact.
The dynamic interaction between the tumor microenvironment and immune cell infiltration is highly complex and crucial for understanding the diverse aspects of cancer pathogenesis, progression stages, and patient prognosis[54–57]. Our study observed a close relationship between the activity of the HSPD1 gene and immune cell properties. HSPD1 gene expression exhibited a significant positive correlation with NK CD56bright cells, T helper cells, and Th2 cells, while concurrently showing a significant negative correlation with Mast cells, iDCs, Cytotoxic cells, Neutrophils, and DCs. Koneva et al.[58] extensively documented the diversity of infiltrating lymphocytes in HNSCC and provided insights into the functions and characteristics of different lymphocyte subtypes. Studies have indicated that a higher infiltration ratio of CD4 + to CD8 + T cells is strongly associated with poor prognosis in patients[59]. However, further in-depth exploration of the mechanisms underlying HSPD1's role in HNSCC remains a critical area for urgent research.
The study's findings underscore a strong association between high HSPD1 gene expression and poor prognosis in HNSCC patients, highlighting the pivotal role of HSPD1 in the disease's development and progression. However, the exact function and mechanisms by which HSPD1 contributes to HNSCC pathogenesis remain subjects of ongoing and in-depth exploration. Comprehensive analysis and elaboration of the specific actions and molecular pathways involving the HSPD1 gene in promoting HNSCC have not yet been fully achieved. Demonstrating the carcinogenic potential of HSPD1 in HNSCC remains a critical concern that warrants further investigation in future studies. This study has limitations, particularly regarding the reliance on publicly available databases, necessitating additional verification and data quality assessment. To substantiate these findings, rigorous validation experiments in large patient cohorts are essential. While this study has validated HSPD1 gene expression and some of its functions through in vitro experiments, comprehensive in vivo studies and detailed investigation at the molecular level are indispensable for further elucidating its mechanisms of action.