Cuproptosis signature and PLCD3 predicts immune infiltration and drug responses in osteosarcoma

Abstract

Osteosarcoma (OS) is a cancer that is frequently found in children and adolescents and has made little improvement in terms of prognosis in recent years. A recently discovered type of programmed cell death called cuproptosis is mediated by copper ions and the tricarboxylic acid (TCA) cycle. The expression patterns, roles, and prognostic and predictive capabilities of the cuproptosis regulating genes were investigated in this work. TARGET and GEO provided transcriptional profiling of OS. To find different cuproptosis gene expression patterns, consensus clustering was used. To identify hub genes linked to cuproptosis, differential expression (DE) and weighted gene co-expression network analysis (WGCNA) were used. Cox regression and Random Survival Forest were used to build an evaluation model for prognosis. For various clusters/subgroups, GSVA, mRNAsi, and other immune infiltration experiments were carried out. The drug-responsive study was carried out by the Oncopredict algorithm. Cuproptosis genes displayed two unique patterns of expression, and high expression of FDX1 was associated with a poor outcome in OS patients. The TCA cycle and other tumor-promoting pathways were validated by the functional study, and activation of the cuproptosis genes may also be connected with immunosuppressive state. The robust survival prediction ability of a five-gene prognostic model was verified. This rating method also took stemness and immunosuppressive characteristics into account. Additionally, it can be associated with a higher sensitivity to medications that block PI3K/AKT/mTOR signaling as well as numerous chemoresistances. U2OS cell migration and proliferation may be encouraged by PLCD3. The relevance of PLCD3 in immunotherapy prediction was verified. The prognostic significance, expressing patterns, and functions of cuproptosis in OS were revealed in this work on a preliminary basis. The cuproptosis-related scoring model worked well for predicting prognosis and chemoresistance.

Construction and validation of a novel cuproptosis-mitochondrion prognostic model related with tumor immunity in osteosarcoma

“…Our study found that FDX1 was associated with poor prognosis, suggesting FDX1 might participate in tumorigenesis and development of osteosarcoma. According to some research, FDX1 was strongly expressed in osteosarcoma tissue, and patients who had high levels of FDX1 expression had a bad prognosis [ 41 , 42 ]. Furthermore, there are no literature findings on FDX1 migration and proliferation in osteosarcoma.…”

Identification and validation of a fatty acid metabolism gene signature for the promotion of metastasis in liver cancer

“…After filtering using the LASSO algorithm, three core genes remained: PLCD3, MRPL35 and CYP2S1. Studies have reported the tumor-promotive role of PLCD3 in thyroid cancer ( 32 ) and osteosarcoma ( 33 ), the role of MRPL35 in gastric ( 34 ) and colorectal ( 35 ) cancer, and the role of CYP2S1 in breast ( 36 ) and lung ( 37 ) cancer. Consistent with this, the group with high WF scores, calculated for the three genes, showed significantly worse outcomes compared with those with low WF scores.…”

The role of programmed cell death in osteosarcoma: From pathogenesis to therapy

“…Although there are fewer studies related to cuproptosis and OS, it has been experimentally demonstrated that cuproptosis can promote cancer generation by promoting certain genes that induce cancer production, for example, TGF‐beta, Wnt/beta‐catenin, and p53 signaling. 110 Research has shown that the NGX6 can inhibit the Wnt/nt/wn that the NGX6 can to inhibit cancer cell metastasis. It has been demonstrated that high‐risk cuproptosis‐related Lncs (CRLncs) can downregulate immune cell function, which increases the risk of osteosarcoma, while low‐risk CRLncs decrease the risk of osteosarcoma.…”

“… 111 Different cuproptosis‐related genes (CRGs) have different effects on osteosarcoma, for example, FDX1 expression contributes to tumor cell survival and drug resistance, and FDX1 can also promote the osteosarcoma cell metastasis but not related to the cancer cell proliferation and the overexpression of FDX1 can also inhibit the tumor immune microenvironment (TIM). 110 , 111 TOMM20 contributes to colon cancer cell invasion suppressing the activity of immune cells such as CD8 T cells and CD4 T cells, aiding cancer cells in evading the immune system. Additionally, overexpression of TOMM20 can contribute to the development of drug resistance in tumor cells against immune‐based therapies, thus impacting tumor treatment.…”

“…Experimental evidence suggests that mitochondria‐dependent malignancies can be treated by copper death. Although there are fewer studies related to cuproptosis and OS, it has been experimentally demonstrated that cuproptosis can promote cancer generation by promoting certain genes that induce cancer production, for example, TGF‐beta, Wnt/beta‐catenin, and p53 signaling 110 . Research has shown that the NGX6 can inhibit the Wnt/nt/wn that the NGX6 can to inhibit cancer cell metastasis.…”