The biological significance of cuproptosis-key gene MTF1 in pan-cancer and its inhibitory effects on ROS-mediated cell death of liver hepatocellular carcinoma

Abstract

Metal regulatory transcription factor 1 (MTF1) has been reported to be correlated with several human diseases, especially like cancers. Exploring the underlying mechanisms and biological functions of MTF1 could provide novel strategies for clinical diagnosis and therapy of cancers. In this study, we conducted the comprehensive analysis to evaluate the profiles of MTF1 in pan-cancer. For example, TIMER2.0, TNMplot and GEPIA2.0 were employed to analyze the expression values of MTF1 in pan-cancer. The methylation levels of MTF1 were evaluated via UALCAN and DiseaseMeth version 2.0 databases. The mutation profiles of MTF1 in pan-cancers were analyzed using cBioPortal. GEPIA2.0, Kaplan–Meier plotter and cBioPortal were also used to explore the roles of MTF1 in cancer prognosis. We found that high MTF1 expression was related to poor prognosis of liver hepatocellular carcinoma (LIHC) and brain lower grade glioma (LGG). Also, high expression level of MTF1 was associated with good prognosis of kidney renal clear cell carcinoma (KIRC), lung cancer, ovarian cancer and breast cancer. We investigated the genetic alteration and methylation levels of MTF1 between the primary tumor and normal tissues. The relationship between MTF1 expression and several immune cells was analyzed, including T cell CD8 + and dendritic cells (DC). Mechanically, MTF1-interacted molecules might participate in the regulation of metabolism-related pathways, such as peptidyl-serine phosphorylation, negative regulation of cellular amide metabolic process and peptidyl-threonine phosphorylation. Single cell sequencing indicated that MTF1 was associated with angiogenesis, DNA repair and cell invasion. In addition, in vitro experiment indicated knockdown of MTF1 resulted in the suppressed cell proliferation, increased reactive oxygen species (ROS) and promoted cell death in LIHC cells HepG2 and Huh7. Taken together, this pan-cancer analysis of MTF1 has implicated that MTF1 could play an essential role in the progression of various human cancers.

Cuproptosis in cancer: biological implications and therapeutic opportunities

“…Recent studies by Song et al. substantiate the theory that MTF1 knockdown curbs cell proliferation, escalates ROS, and exacerbates cell death in HepG2 and Huh7 [ 149 ]. Furthermore, they found that high MTF1 expression was linked to a poor prognosis for liver HCC and brain lower-grade glioma (LGG) but a better prognosis for KIRC, lung, ovarian, and breast cancer [ 126 ].…”

“…Higher levels of DLAT expression were correlated with elevated PD-L1 levels [ 140 – 142 ] PAAD Up Elevated DLAT expression in PAAD was correlated with increased resistance to a range of chemotherapeutics, including gemcitabine, irinotecan, 5-fluorouracil, and oxaliplatin [ 143 ] KIRC Down High expression levels of DLAT were linked with good OS in patients with KIRC [ 140 , 142 , 144 ] LUAD Up High expression levels of DLAT were associated with worse outcomes in patients with LUAD [ 145 ] GLS PCA Up High expression of GLS was significantly associated with Gleason score and tumor stage [ 146 ] CDNK2A Pan-cancer CDKN2A mutations that prevent its binding to CDKs can lead to uncontrolled growth in various tumors, including NSCLC, PAAD, HNSCC, breast, and ovarian cancers. Epigenetic reduction of CDKN2A level changed the expression of cancer-related oncogenes or tumor suppressor genes and promoted tumorigenesis [ 147 ] MTF1 Gastric cancer Down High MTF1 expression was associated with longer OS in patients with gastric cancer [ 148 ] LIHC Up High MTF1 expression was related to poor prognosis in patients with LIHC [ 149 , 150 ] LGG Up High ...…”

“…Furthermore, they found that high MTF1 expression was linked to a poor prognosis for liver HCC and brain lower-grade glioma (LGG) but a better prognosis for KIRC, lung, ovarian, and breast cancer [ 126 ]. Single-cell sequencing revealed that MTF1 was implicated in several tumor development-associated processes, including DNA repair, angiogenesis, and cell invasion [ 149 ]. Zhang et al.…”

Clinical features and molecular landscape of cuproptosis signature‐related molecular subtype in gastric cancer

“…Dysregulation of SLC31A1, ATP7B , and ATP7A has been implicated in colorectal cancer and can affect copper homeostasis and tumor growth [ 43 , 44 ]. MTF1 is a gene that encodes the metal‐responsive transcription factor 1, which plays a role in regulating the expression of genes involved in metal ion homeostasis and oxidative stress response [ 45 ]. It can affect cellular response to oxidative stress and DNA damage.…”

Revolutionizing breast cancer treatment: Harnessing the related mechanisms and drugs for regulated cell death (Review)

“…Recent studies have shed light on the crucial role of MTF1 , a gene associated with cuproptosis. Notably, its expression differs in tumor cells compared to normal cells, and reducing MTF1 levels can elevate ROS production and initiate cuproptosis ( 165 ). Similarly, the buildup of ROS is crucial for ferroptosis, another form of RCD.…”