With a high rate of morbidity and a tendency for early metastases, ESCC is a potentially fatal cancer [22]. The prognosis for patients with ESCC is still dire because conventional anti-tumor medications have minimal efficacy against it [23]. Although early detection of esophageal cancer has been made possible by endoscopy, less than 20% of patients will survive the disease for five years, so developing novel treatment strategies is vital [24]. LncRNAs have been linked to human disorders, particularly cancers, according to a large body of research [25–27]. Previous research has examined the close connection between MIR210HG and cancer. For example, LncRNA MIR210HG has been shown to inhibit SH3GL3 transcription, which promotes lung cancer cell invasion, migration, and proliferation [28], Similarly, LncRNA MIR210HG has been shown to facilitate the malignant proliferation of glioma cells [29]. But there is still undiscovered territory in the field of ESCC research.
For the first time, we found in this study that patient survival is strongly correlated with high expression of the lncRNA MIR210HG, which can reduce ESCC. Moreover, to deepen our understanding of the mechanisms by which lncRNA MIR210HG affects ESCC, we performed enrichment analysis on the top 300 genes closely associated with its expression. Positive correlations between the P53 signaling pathway and lncRNA MIR210HG were discovered. One of the most significant tumor suppressor genes in humans is TP53, which is frequently referred to as the "guardian gene"[30]. By encouraging DNA repair or the regulated death of aberrant cells, p53 activation helps to prevent the onset and progression of cancer[31]. Moreover, research has demonstrated that p53 can stop tumor immune evasion [32].
Numerous studies have shown that p53 is essential for numerous processes, including ferroptosis, autophagy, cell metabolism, and metabolism [33]. An intriguing discovery was made by this study: there was a considerable drop in the expression of p62 protein, which suggests that tumor cells had increased autophagy. The expression of p53 and phospho-p53, as well as the autophagy-related proteins Beclin-1 and LC3B-II, were all markedly upregulated in ESCC cells due to the elevated expression of the lncRNA MIR210HG. Next, we employed a p53 inhibitor (PFT-α) to verify if the alterations in autophagy levels in ESCC cells were brought about by the modification of p53 by lncRNA MIR210HG. PFT-α successfully inhibited the increased autophagy levels in ESCC cells with overexpressed lncRNA MIR210HG. These findings reveal that elevated autophagy levels in ESCC cells are strongly correlated with high expression of lncRNA MIR210HG, suggesting that autophagy plays a role in the mechanism by which lncRNA MIR210HG influences ESCC advancement. In a similar vein, we investigated apoptosis in parallel. Finally, we further validated our findings in mouse specimens. To the best of our knowledge, this is the first evidence that the P53 signaling pathway can be used by lncRNA MIR210HG to affect autophagy and apoptosis in ESCC. Thorough investigation into the processes underlying the relationship between autophagy or apoptosis and lncRNA MIR210HG could lead to fresh perspectives and recommendations for the management of ESCC.
Numerous immune and stromal cells comprise the tumor microenvironment, and they are important for both the course of cancer and the response to treatment [34, 35]. During tumor progression, regulatory T cells (Tregs) can suppress tumor immunity, and a high infiltration of Tregs in the TME often indicates a poor prognosis[36]. According to our findings, there were more immunosuppressive cells, such as Tregs, in the lncRNA MIR210HG low expression group. This resulted in the creation of an immunosuppressive milieu that impedes the clearance of tumors. Currently, monoclonal antibodies targeting immune checkpoint molecules have achieved significant breakthroughs in cancer therapy. Taking CCL2 and PD-L1 as examples, their targeting has shown encouraging results in the treatment of ESCC[37]. We found that there were notable distinctions between the expression levels of lncRNA MIR210HG at high and low levels in different immunological checkpoints.
Differential expression of lncRNA MIR210HG also aids in selecting therapeutic drugs for patients with ESCC. For example, in this investigation, we discovered that patients with low expression of lncRNA MIR210HG responded better to Cytarabine, Vincristine, Daporinad, AZD2014, and AZD5153. Previous research has shown that Cytarabine can enhance the therapeutic effect on lung cancer and mitigate the side effects of radiotherapy[38]. Vincristine is a naturally occurring vinca alkaloid found in the periwinkle plant and is an anti-mitotic compound that disrupts microtubule dynamics to halt the cell cycle. Currently, Vinorelbine and Rituximab are widely used in clinical cancer treatments[39]. Better outcomes in cancer therapy may result from a deeper comprehension of the mechanisms underlying these medications and the creation of sensible usage methods.
There are still certain limitations even though our study used strict selection criteria during the analysis and has important clinical implications. First of all, there has to be more experimentation and confirmation with a bigger cohort due to the small sample size that was analyzed. Secondly, while the drug sensitivity analysis identified potential therapeutics, the mechanisms of their effects on ESCC remain unknown and warrant further investigation.
In summary, our study is the first to reveal that lncRNA MIR210HG is underexpressed in ESCC and that this low expression is highly linked with patient survival. The lncRNA MIR210HG has the ability to suppress ESCC cell migration, invasion, and proliferation. Furthermore, through the P53 signaling pathway, increased expression of the lncRNA MIR210HG encourages autophagy and death in ESCC cells. In addition, we conducted drug sensitivity predictions and immune cell infiltration analyses for ESCC patients with different expressions of lncRNA MIR210HG, finding that Cytarabine and Vincristine have better therapeutic effects on patients with low expression of lncRNA MIR210HG, providing a theoretical basis for personalized management and treatment of ESCC patients.