The prognosis for patients with advanced and metastatic LUAD remains poor [3]. Therefore, integrating multiple biomarkers and assessing their prognostic accuracy, immune relevance and sensitivity can effectively personalize treatment plans [4]. Copper has been shown to be associated with cancer. Lately research have indicated that copper amass in bioplast triggers mitochondrial lipid acylated proteins concentration and loss of Fe-S cluster proteins, leading to proteotoxic stress-induced death, known as Cuproptosis [1]. Cuproptosis different from others, It relies on mitochondrial respiration rather than adenosine triphosphate (ATP) production [5]. Thus, Cuproptosis will probably be an effective therapeutic target for numerous cancers.
Furthermore, lncRNAs effect cancer development and treatment traverse biological means [19]. Meanwhile lncRNAs accounting for more than 80% in RNAs [20]. So lncRNAs play significant role in cancer moderation effects. A research indicated that lncRNA KTN1-AS1 conduct a pre-oncogene in lung cancer and can monitor cell cycle-dependent kinase (CDK) 1 to effect the cell cycle, suggesting that lncRNAs probably a new cancer biomarker and therapeutic target [21]. Therefore, Cupr-RLs may be used to predict survival and immunotherapy response in LUAD. Although there are clinical trials of the copper ion carrier small molecule anticancer drug elesclomol [22]. Their results were not satisfactory. However, the synergistic regulation of Cupr-RLs in LUAD calls for further investigated and unveil latent prognostic indicators.
Our currently research appraised Cupr-RLs traversed co-expression assay. Through further assays (uni-Cox and LASSO Cox analysis),9 Cupr-RLs were ascertained as carrying prognostic merits (AC011773.3, AC097505.1, AC084871.3, DUBR, AL133304.3, AP003721.1, AC145285.2, C5orf66-AS1AL031985.3). Previous studies have reported different types of predicted lncRNA profiles in LUAD [23, 24]. In Huang's study, the highest AUC of the lncRNA signals associated with related to immunity and iron removal in the past 5 years was 0.761. the minimum AUC in our study was 0.692, suggesting that the signals of Cupr-RLs have strong predictive ability [25]. ROC, survival, histogram and heatmap analysis displayed the prognosis of the nine Cupr-RLs in two groups, as well as the different stages patients were accurately forecast the prognosis. These lncRNAs are independent of rest common clinical features as prognostic elements.
Especially, these newly discovered Cupr-RLs support us discover approach means for cancer remedy. We classified LUAD patients into low-risk and high-risk cohorts according to the median. ROC curves were used to testing the prognostic fidelity of risk scores. Identified risk score may be a forecasting prognosis criterion. Afterwards, we structured a nomogram and calibration curve to projecting that. Principal component analysis showed the nine Cupr-RLs discriminate between two risk groups effectively. High-risk groups we identified were predicted poor prognosis. GO analysis shows that immune response and lipid transport protein activity are closely related to Cupr-RLs. KEGG analysis showed that the complement cascade, the PPAR signal pathway, and the Wnt signal pathway were the most active in the Cupr-RLs. The complement and coagulation cascades, Wnt signal pathway and PPAR signal pathway are widely present in various cells and activating downstream signal molecules that participant majority cell functions, which is regarded as a major pathway for cancer cell survival [26, 27].
The major contribution in our research certificated the relation between Cupr-RLs signal and tumor microenvironment (TME). Notably, TME plays a crucial role in tumor progression, immunotherapy response and OS[28]. Complement and coagulation cascades are vital regulators in immune system, enabling short-range communication between immune system cells [26]. Typically, immune cells infiltration in TME varies with tumor progression. Sierra [29] found that NK cells infiltration impairs body's immunomodulation.As mentioned earlier, the TIDE algorithm is used to evaluating the Immune checkpoint inhibitors (ICI) therapy response. Higher the TIDE score, the greater possibility of immune escape, which implied that patients receiving ICI treatment have finite reaction and shorter survival time. These outcomes indicate Cuproptosis may be probably involved in tumor immune microenvironment of LUAD, traverse blocking immune reaction. And we validated the fidelity of the risk pattern.
TP53 had a higher mutation frequency in LUAD patients, and a higher mutation frequency and higher TMB in low-risk group, further Indicating that immunotherapy is more efficacious in low-risk group. There was a significant difference in IC50 between two groups using the six drugs. In our study, the immunosuppressive drugs CP724714 and gefitinib have demonstrated a more significant benefit in low-risk population. As with the similar immunosuppressive drug pazopanib, previous clinical trials have confirmed that greater efficacy was achieved in the low-risk group [30]. In our research, sirolimus, Roscovitine, BX795, and vincristine, which are associated with autophagy, apoptosis, and death, all confirmed more prominent benefits in high-risk group. Sirolimus, as an immunosuppressive drug, is not only a potent specific mTOR but also an autophagy activator. It may be associated with copper metabolism-induced cell death [31]. According to our findings, among antitumor drugs that related to programmed cell death, apoptosis and autophagy, the group with higher risk scores had lower IC50. This further suggests that these drugs may conclude Cuproptosis pathways which leading to cell death. Therefore, Cuproptosis and immunotherapy provides a prominent help for personalized treatment of clinical patients in the future.
ICI treatment was efficacious for LUAD patients which recurrent or refractory [18].However, the OS for ICI therapy remains low, it is urgent to determine who will best benefit from ICI. Cupr-RLs、IRGPI can be used to predict that. We applied WGCNA which is a virtual method to identify key immune-related hub genes (JUND, FLT4, THRB, VIPR1) that affect patients' OS and constructed an IRGPI, and found that in TCGA and GEO cohorts patients with a high IRGPI had a higher survival rate.
IRGPI consists of four genes: JUND, FLT4, THRB, VIPR1. The transcription factor (JUND) expressed by the proto-oncogene JUND can activate the expression of MMP13 (Matrix Metalloproteinase 13) and urokinase receptor analogue, MMP and urokinase, as protein hydrolases, participate invasion and metastasis in various tumor cells. FLT4 tripper angiogenesis in the tissue. Thyroid hormone receptor (THR), also known as c-erbA-2, is a ligand-dependent intracellular protein that stimulates the transcription of specific genes upon activation by the corresponding hormone by binding specific DNA sequences known as hormone-responsive elements. VIPR1 Gene encodes the receptor for vasoactive intestinal peptide, a small neuropeptide. Vasoactive intestinal peptide is participate in smooth muscle relaxation, exocrine and endocrine secretion, and transportation ions in epithelial cells of lungs and intestines. So IRGPI is a biomarker correspondent to active immunity and tumor suppression. From the results of the study analysis, we found that the samples with high IRGPI overlapped with Cupr RLs in terms of functional enrichment, so we further found that Cupr genes interacted with IRGs (JUND, FLT4, THRB, VIPR1) in immunotherapy of lung adenocarcinoma, so we further explored the relation between IRGs and Cupr-genes. According to the result IRGs interacted with the Cupr-gene completed the relevant role in LUAD immunotherapy, they both can affect prognosis of LUAD immunotherapy. Cupr-RLs and IRGPI need to be further analyzed and explored in the future.
Cupr-RLs as well as IRGPI are significant in cancer treatment. We explored Cuproptosis biomarkers for LUAD prognosis and the impact of IRGPI and Cupr-RLs on LUAD immunotherapy. From a future perspective antitumor drugs should target cancer stem cells to overcome resistance. Cancer cells are usually preferentially induced by Cuproptosis which are promising prospects in this context [32, 33]. Therefore, there is an urgent need to deepen the understanding of Cuproptosis. Meanwhile immunotherapy, targeted therapy, and gene therapy will be the future of personal treatment for patients.
CONCLUSION: The risk profile of nine lncRNAs related to Cuproptosis helps to assess the prognosis and therapy efficacy of LUAD. The impact of LUAD immunotherapy by IRGPI and Cupr-RLs may improve the treatment regimen and provide a personalised treatment, which can be further applied in clinical practice.