Melanoma is among the 10 most prevalent malignant tumors, posing a significant threat to human health. A detailed understanding of the molecular mechanisms driving its progression is crucial for advancing treatment strategies and outcomes. Based on bioinformatic analysis and experimental validation, this study identified mitochondrial carrier homolog 2 (MTCH2) as a key regulator of melanoma proliferation. Mechanistically, MTCH2 enhanced the expression and nuclear translocation of nuclear factor (erythroid-derived-2)-like 2 (NRF2), which up-regulated ribonucleotide reductase subunit M1 (RRM1) expression, thereby promoting melanoma cell proliferation. Targeting RRM1 in combination with dacarbazine significantly inhibited tumor growth in nude mouse xenograft models. These findings elucidate a mechanistic link between MTCH2 and the NRF2-RRM1 axis in melanoma proliferation and highlight potential therapeutic targets for intervention.

Gliomas are aggressive brain tumors known for their poor prognosis and resistance to standard treatment options. Ferroptosis is an iron-dependent form of regulated cell death that has emerged as a promising target for cancer treatment. This study examined how the methyltransferase-like 3/YTH domain family protein 1 (METTL3/YTHDF1) axis influences ferroptosis and glioma progression by stabilizing mitochondrial carrier homolog 2 (MTCH2) messenger RNA (mRNA).

MTCH2 expression in glioma tissues and cell lines was evaluated through quantitative real-time polymerase chain reaction (PCR) and western blot analyses. To assess the effects of MTCH2 knockdown and overexpression on glioma cell functions, we performed a series of functional assays, including cell viability, colony formation, and measurements of lipid reactive oxygen species (lipid ROS) and malondialdehyde (MDA) levels. Additionally, we conducted RNA immunoprecipitation (RIP) and RNA stability assays to explore the underlying mechanisms governing the interaction between METTL3, YTHDF1, and the stability of MTCH2 mRNA.

MTCH2 was significantly upregulated in glioma tissues and cell lines. Silencing of MTCH2 resulted in decreased glioma cell proliferation and induced ferroptosis, as evidenced by increased lipid peroxidation and ROS accumulation. Conversely, overexpression of MTCH2 enhanced glioma cell survival and reduced ferroptosis. METTL3-mediated N6-methyladenosine (m6A) modification enhanced MTCH2 mRNA stability by enabling YTHDF1 to bind and protect the modified mRNA from degradation.

The METTL3/YTHDF1/MTCH2 axis plays a critical role in glioma progression by inhibiting ferroptosis and promoting tumor cell survival. Targeting this pathway may provide a new and effective treatment strategy for glioma patients.

Discovering new molecular targets for non-small cell lung cancer (NSCLC) is critically important. Enhanced mitochondrial function can promote NSCLC progression by enabling metabolic reprogramming, resistance to apoptosis, and increased cell proliferation. Mitochondrial carrier homolog 2 (MTCH2), located in the outer mitochondrial membrane, is pivotal in regulating mitochondrial activities. This study examines MTCH2 expression and its functional role in NSCLC. Bioinformatic analysis showed that MTCH2 is overexpressed in NSCLC tissues, correlating with poor prognosis and other key clinical parameters of the patients. In addition, single-cell sequencing data revealed higher MTCH2 expression levels in cancer cells of NSCLC tumor mass. Moreover, MTCH2 is also upregulated in locally-treated NSCLC tissues and multiple primary/established human NSCLC cells. In various NSCLC cells, silencing MTCH2 via targeted shRNA or knockout (KO) using the CRISPR/Cas9 method significantly hindered cell proliferation, migration and invasion, while inducing apoptosis. MTCH2 knockdown or KO robustly impaired mitochondrial function, as indicated by reduced mitochondrial respiration, decreased complex I activity, lower ATP levels, lower mitochondrial membrane potential (mitochondrial depolarization), and increased reactive oxygen species (ROS) production. Conversely, ectopic overexpression of MTCH2 in primary NSCLC cells enhanced mitochondrial complex I activity and ATP production, promoting cell proliferation and migration. In vivo, the intratumoral injection of MTCH2 shRNA adeno-associated virus (aav) impeded the growth of subcutaneous xenografts of primary NSCLC cells in nude mice. In MTCH2 shRNA aav-injected NSCLC xenograft tissues, there was decreases in MTCH2 expression, mitochondrial complex I activity, ATP content, and the glutathione (GSH)/glutathione disulfide (GSSG) ratio, but increase in thiobarbituric acid reactive substances (TBAR) activity. Additionally, MTCH2 silencing led to reduced Ki-67 staining but increased apoptosis in NSCLC xenografts. Collectively, these findings demonstrate that overexpressed MTCH2 promotes NSCLC cell growth potentially through the maintenance of mitochondrial hyper-function, highlighting MTCH2 as a novel and promising therapeutic target for treating this disease.

We here investigate the expression of the mitochondrial carrier homolog 2 (MTCH2) and its potential function in castration-resistant prostate cancer (CRPC). Bioinformatic analyses reveal that MTCH2 overexpression is associated with critical clinical parameters of prostate cancer. Single-cell sequencing data indicate elevated MTCH2 expression in the prostate cancer epithelium. MTCH2 is also upregulated in locally treated CRPC tissue and various primary human CRPC cells. Using genetic silencing via shRNA and knockout (KO) through the CRISPR-sgRNA approach, we showed that the depletion of MTCH2 impaired mitochondrial function, resulting in a reduced oxygen consumption rate, diminished complex I activity, and decreased ATP levels, mitochondrial depolarization, and increased reactive oxygen species production in primary CRPC cells. The silencing or KO of MTCH2 significantly inhibited cell viability, proliferation, and migration, together with a marked increase in apoptosis in the primary CRPC cells. In contrast, ectopic expression of MTCH2 provided CRPC cells with pro-tumorigenic properties, enhancing ATP production and promoting cell proliferation and migration. MTCH2 silencing also markedly inhibited the growth of subcutaneous xenografts of the primary CRPC cells in nude mice. The MTCH2-silenced xenografts exhibited increased apoptosis, elevated lipid peroxidation, and decreased ATP levels. These results provide new insights into the role of MTCH2 in supporting mitochondrial function and CRPC progression.

Cancer cells undergo remarkable metabolic changes to meet their high energetic and biosynthetic demands. The Warburg effect is the most well-characterized metabolic alteration, driving cancer cells to catabolize glucose through aerobic glycolysis to promote proliferation. Another prominent metabolic hallmark of cancer cells is their increased reliance on glutamine to replenish tricarboxylic acid (TCA) cycle intermediates essential for ATP production, aspartate and fatty acid synthesis, and maintaining redox homeostasis. In this context, mitochondria, which are primarily used to maintain energy homeostasis and support balanced biosynthesis in normal cells, become central organelles for fulfilling the heightened biosynthetic and energetic demands of proliferating cancer cells. Mitochondrial coordination and metabolite exchange with other cellular compartments are crucial. The human SLC25 mitochondrial carrier family, comprising 53 members, plays a pivotal role in transporting TCA intermediates, amino acids, vitamins, nucleotides, and cofactors across the inner mitochondrial membrane, thereby facilitating this cross-talk. Numerous studies have demonstrated that mitochondrial carriers are altered in cancer cells, actively contributing to tumorigenesis. This review comprehensively discusses the role of SLC25 carriers in cancer pathogenesis and metabolic reprogramming based on current experimental evidence. It also highlights the research gaps that need to be addressed in future studies. Understanding the involvement of these carriers in tumorigenesis may provide valuable novel targets for drug development.

Ovarian cancer (OC) is a gynecological malignancy that ranks among the most common female cancers worldwide and notably reduces a patient's quality of life. Mitochondrial carrier homology 2 (MTCH2) is a mitochondrial outer membrane protein that serves a regulatory role in mitochondrial metabolism and cell death. The precise contribution and underlying molecular pathways of MTCH2 in the context of OC development is currently unclear. The present study aimed to investigate the roles of MTCH2 in the energy metabolism, cell proliferation and metastatic potential of OC cells and evaluate the regulatory relationship between MTCH2, aminoacyl transfer RNA synthetase-interacting multifunctional protein 2 (AIMP2) and claudin-3. An analysis of 67 patients with high-grade serous OC demonstrated increased expression levels of MTCH2, AIMP2 and claudin-3 in OC tumor tissue samples compared with in corresponding normal tissues adjacent to OC tissue samples. MTCH2 overexpression was significantly associated with the International Federation of Gynecology and Obstetrics stage and tumor differentiation of the OC tumor samples. In vitro experiments using the SK-OV-3 OC cell line demonstrated that MTCH2 exerts a regulatory effect on the cell proliferation, invasion and migratory capabilities of these cells. Knockdown of MTCH2 reduced ATP production, induced mitochondrial dysfunction and promoted cytoskeleton remodeling and apoptosis in SK-OV-3 OC cells. In addition, MTCH2 knockdown downregulated the expression levels of both claudin-3 and AIMP2 proteins. Knockdown of AIMP2 inhibited the regulatory effect of MTCH2. Co-immunoprecipitation experiments demonstrated that MTCH2 interacts with AIMP2 and claudin-3. The present study provides novel insights into the treatment of OC metastasis, as MTCH2 was demonstrated to serve roles in the progression of OC cells through the regulation of claudin-3 via AIMP2, which could provide novel insights into the treatment of ovarian cancer metastasis.

This study aims to develop brain-targeted temozolomide (TMZ) nanograins using the biodegradable polymer material PEG-PLA as a carrier. The model drug TMZ was encapsulated within the polymer using targeted nanotechnology. Key characteristics such as appearance, particle size, size distribution, drug loading capacity, in vitro release rate, stability, and anti-tumor effects were systematically evaluated through in vitro experiments.

Transmission electron microscopy (TEM) and Malvern size analyzer were employed to observe the morphological and particle size features of the TMZ nanospheres at various time points to assess stability. The effects of TMZ nanograins on glioma cell viability and apoptosis were evaluated using MTT assays and flow cytometry.

The targeted TMZ nano-micelles were successfully synthesized. After loading and targeted modifications, the particle size increased from 50.7 to 190 nm, indicating successful encapsulation of TMZ. The average particle size of the nano-micelles remained stable around 145 ± 10 nm at 1 day, 15 days, and 30 days post-preparation. The release rate of the nano-micelles was monitored at 2 h, 12 h, 24 h, and 48 h post-dialysis, ultimately reaching 95.8%. Compared to TMZ alone, the TMZ-loaded PEG-PLA nano-micelles exhibited enhanced cytotoxicity and apoptosis in glioma cells. This was accompanied by increased mitochondrial membrane potential and reactive oxygen species (ROS) levels following treatment with the TMZ nano-micelles.

TMZ-loaded nano-micelles demonstrated a gradual release profile and significantly enhanced inhibitory effects on human glioma U251 cells compared to TMZ alone. The findings suggest that TMZ-loaded PEG-PLA nano-micelles may offer a more effective therapeutic approach for glioma treatment.

Mitochondrial carrier homolog 2 (MTCH2) is a member of the solute carrier 25 family, located on the outer mitochondrial membrane. MTCH2 was first identified in 2000. The development in MTCH2 research is rapidly increasing. The most well-known role of MTCH2 is linking to the pro-apoptosis BID to facilitate mitochondrial apoptosis. Genetic variants in MTCH2 have been investigated for their association with metabolic and neurodegenerative diseases, however, no intervention or therapeutic suggestions were provided. Recent studies revealed the physiological and pathological function of MTCH2 in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction via regulating mitochondrial apoptosis, metabolic shift between glycolysis and oxidative phosphorylation, mitochondrial fusion/fission, epithelial-mesenchymal transition, etc. This review endeavors to assess a total of 131 published articles to summarise the structure and physiological/pathological role of MTCH2, which has not previously been conducted. This review concludes that MTCH2 plays a crucial role in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction, and the predominant molecular mechanism is regulation of mitochondrial function. This review gives a comprehensive state of current knowledgement on MTCH2, which will promote the therapeutic research of MTCH2.

The MTCH2 protein is located on the mitochondrial outer membrane and regulates mitochondria-related cell death. This study set out to investigate the role of MTCH2 in the underlying pathophysiological mechanisms of breast cancer (BC). MTCH2 expression levels in BC were analyzed using bioinformatics prior to verification by cell lines in vitro. Experiments of over-expression and siRNA-mediated knockdown of MTCH2 were conducted to assess its biological functions, including its effects on cellular proliferation and cycle progression. Xenografts were utilised for in vivo study and signaling pathway alterations were examined to identify the mechanisms driven by MTCH2 in BC proliferation and cell-cycle regulation. MTCH2 was up-regulated in BC and correlated with patients' overall survival. Over-expression of MTCH2 promoted cellular proliferation and cycle progression, while silencing MTCH2 had the opposite effect. Xenograft experiments were utilised to confirm the in vitro cellular findings and it was identified that the PI3K/Akt signaling pathway was activated by MTCH2 over-expression and suppressed by its silencing. Moreover, the activation of IGF-1R rescued cellular growth and cycle arrest induced by MTCH2-silencing. Overall, this study reveals that expression of MTCH2 in BC is upregulated and potentiates cellular proliferation and cycle progression via the PI3K/Akt pathway.

The precise role of mitochondrial carrier homolog 2 (MTCH2) in promoting malignancy in gastric mucosal cells and its involvement in gastric cancer cell metastasis have not been fully elucidated.

To determine the role of MTCH2 in gastric cancer.

We collected 65 samples of poorly differentiated gastric cancer tissue and adjacent tissues, constructed MTCH2-overexpressing and MTCH2-knockdown cell models, and evaluated the proliferation, migration, and invasion of human gastric epithelial cells (GES-1) and human gastric cancer cells (AGS) cells. The mitochondrial membrane potential (MMP), mitochondrial permeability transformation pore (mPTP) and ATP fluorescence probe were used to detect mitochondrial function. Mitochondrial function and ATP synthase protein levels were detected via Western blotting.

The expression of MTCH2 and ATP2A2 in gastric cancer tissues was significantly greater than that in adjacent tissues. Overexpression of MTCH2 promoted colony formation, invasion, migration, MMP expression and ATP production in GES-1 and AGS cells while upregulating ATP2A2 expression and inhibiting cell apoptosis; knockdown of MTCH2 had the opposite effect, promoting overactivation of the mPTP and promoting apoptosis.

MTCH2 can increase the malignant phenotype of GES-1 cells and promote the proliferation, invasion, and migration of gastric cancer cells by regulating mitochondrial function, providing a basis for targeted therapy for gastric cancer cells.

The mitochondrial carrier system is in charge of small molecule transport between the mitochondria and the cytoplasm as well as being an integral portion of the core mitochondrial function. One member of the mitochondrial carrier family of proteins, mitochondrial carrier homolog 2 (MTCH2), is characterized as a critical mitochondrial outer membrane protein insertase participating in mitochondrial homeostasis. Accumulating evidence demonstrate that MTCH2 is integrally linked to cell death and mitochondrial metabolism, and its genetic alterations cause a variety of disease phenotypes, ranging from obesity, Alzheimer's disease, and tumor. To provide a comprehensive insight into the current understanding of MTCH2, we present a detailed description of the physiopathological functions of MTCH2, ranging from apoptosis, mitochondrial dynamics, and metabolic homeostasis regulation. Moreover, we summarized the impact of MTCH2 in human diseases, and highlighted tumors, to assess the role of MTCH2 mutations or variable expression on pathogenesis and target therapeutic options.

Glioma, particularly glioblastoma multiforme (GBM), is a highly aggressive and lethal primary brain tumor with poor prognosis. Metabolic reprogramming and endoplasmic reticulum (ER) stress are two crucial factors contributing to glioma pathogenesis. However, the intricate coordination between these processes remains incompletely understood. Here, we conducted an integrative analysis to elucidate the nodal role of DNA Damage Inducible Transcript 3 (DDIT3) to couple metabolisms and stress responses in glioma. We demonstrated a positive association between DDIT3 amplification/enhanced expression with glioma malignancy, indicating its potential as a novel biomarker for prognosis and treatment stratification. Genomic and transcriptomic analyses further revealed the involvement of DDIT3 enhancement in glioma progression. Moreover, immune infiltration analysis showed that distinct DDIT3 expression groups had different immune microenvironment. Finally, in vitro validations confirmed the impact of DDIT3 on proliferation and migration of glioma cells. Our findings provide novel insights into the complex interplay between metabolic reprogramming and ER stress, and defines DDIT3 as a promising therapeutic target in glioma.

Introduction: There is a steady increase in colorectal cancer (CRC) incidences worldwide; at diagnosis, about 20 percent of cases show metastases. The transforming growth factor-beta (TGF-β) signaling pathway is one of the critical pathways that influence the expression of cadherins allowing the epithelial-to-mesenchymal transition (EMT), which is involved in the progression of the normal colorectal epithelium to adenoma and metastatic carcinoma. The current study aimed to investigate the impact of a novel coordination complex of platinum (salicylaldiminato) PT(II) complex with dimethyl propylene linkage (PT-complex) on TGF-β and EMT markers involved in the invasion and migration of the human HT-29 and SW620 CRC cell lines. Methods: Functional study and wound healing assay showed PT-complex significantly reduced cell motility and the migration and invasion of CRC cell lines compared to the untreated control. Western blot performed in the presence and absence of TGF-β demonstrated that PT-complex significantly regulated the TGF-β-mediated altered expressions of EMT markers. Results and Discussion: PT-complex attenuated the migration and invasion by upregulating the protein expression of EMT-suppressing factor E-cadherin and suppressing EMT-inducing factors such as N-Cadherin and Vimentin. Moreover, PT-complex significantly suppressed the activation of SMAD3 in both CRC cell lines. Further, the microarray data analysis revealed differential expression of genes related to invasion and migration. In conclusion, besides displaying antiproliferative activity, the PT complex can decrease the metastasis of CRC cell lines by modulating TGF-β-regulated EMT markers. These findings provide new insight into TGF-β/SMAD signaling as the molecular mechanism involved in the antitumoral properties of novel PT-complex.

Glioma is a highly malignant and unfavorable cancer in the brain. Recent evidence highlights the vital role of cilia-related pathways as novel regulators of glioma development. However, the prognostic potential of ciliary pathways in glioma is still ambiguous. In this study, we aim to construct a gene signature using cilia-related genes to facilitate the prognostication of glioma.

A multi-stage approach was employed to build the ciliary gene signature for prognostication of glioma. The strategy involved the implementation of univariate, LASSO, and stepwise multivariate Cox regression analyses based on TCGA cohort, followed by independent validation in CGGA and REMBRANDT cohort. The study further revealed molecular differences at the genomic, transcriptomic, and proteomic levels between distinct groups.

A prognostic tool utilizing a 9-gene signature based on ciliary pathways was developed to assess the clinical outcomes of glioma patients. The risk scores generated by the signature demonstrated a negative correlation with patient survival rates. The validation of the signature in an independent cohort reinforced its prognostic capabilities. In-depth analysis uncovered distinctive molecular characteristics at the genomic, transcriptomic, and protein-interactive levels in the high- and low-risk groups. Furthermore, the gene signature was able to predict the sensitivity of glioma patients to conventional chemotherapeutic drugs.

This study has established the utility of a ciliary gene signature as a reliable prognostic predictor of glioma patient survival. Findings not only enhance our comprehension of the intricate molecular mechanisms of cilia pathways in glioma, but also hold significant clinical implications in directing chemotherapeutic strategies.

We investigated the somatic mutations and key driving factors of cervical cancer by whole exome sequencing . We found 22,183 somatic single nucleotide variations (SNVs) in 52 paired samples. Somatic SNVs in cervical cancer were significantly higher than those in high-grade intraepithelial lesion and low-grade squamous intraepithelial lesion groups (P < 0.05). C → T/G accounted for 44.12% of base substitution. Copy number variation (false discovery rate < 0.05) was found in 57 chromosome regions. The three regions with significant differences between cervical cancer and non-cervical cancer groups were 1q21.1, 3q26.33, and 13q33.1, covering genes related to tumor proliferation, differentiation, and apoptosis. The frequency of human papillomavirus (HPV) insertion/integration and the number of "tCw" mutations in the cervical cancer group were significantly higher than those in the non-cervical cancer group (P < 0.05). The total number of mutations was positively correlated with the number of "tCw" mutations (R 2 = 0.7967). HPV insertion/integration (OR = 2.302, CI = 1.523-3.589, P = 0.0005), APOBEC enrichment (OR = 17.875, CI = 2.117-150.937, P = 0.001), and HLA-B*39 in HLA-I (OR = 6.435, CI = 0.823-48.919, P = 0.0042) were risk factors for cervical cancer, while HLA-DQB1*05 in HLA-II was a protective factor (OR = 0.426, CI = 0.197-0.910, P = 0.032). Conclusively, HPV insertion/integration, APOBEC mutagenesis, and HLA polymorphisms are high-risk factors for cervical cancer and may be causes of genome instability and somatic mutations. This study provides experimental data for revealing the molecular mechanism of cervical cancer.

Osteosarcoma is the most prevalent primary malignant bone cancer worldwide. Apolipoprotein C1 (APOC1) and mitochondrial carrier homolog 2 (MTCH2) have been identified to be upregulated during the oncogenesis and metastasis of osteosarcoma. The aim of the present study was to explore the role of APOC1 in osteosarcoma progression and the mechanisms associated with MTCH2. APOC1 and MTCH2 expression in osteosarcoma cells was assessed by reverse transcription-quantitative PCR and western blotting. Then, APOC1 was silenced to detect its effect on cell viability, proliferation and apoptosis using Cell Counting Kit-8, a colony formation assay and TUNEL staining, respectively. Transwell and wound healing assays were used to evaluate cell invasion and migration. The interaction between APOC1 and MTCH2 as predicted by the Biological General Repository for Interaction Datasets and the Search Tool for the Retrieval of Interacting Genes/Proteins databases was verified by co-immunoprecipitation assay. Subsequently, rescue experiments were performed to analyze the regulatory effects of APOC1 on MTCH2 in the biological behavior and Warburg effect of osteosarcoma cells. Significantly upregulated APOC1 and MTCH2 expression was found in osteosarcoma SAOS-2 cells. APOC1 silencing attenuated cell viability, inhibited proliferation and promoted cell apoptosis, coupled with the decreased Bcl-2 expression and increased Bax and cleaved-caspase 3 expression. The invasive and migratory capacities of SAOS-2 cells were also suppressed following APOC1 knockdown. Moreover, APOC1 was confirmed to interact with MTCH2 in osteosarcoma cells. MTCH2 upregulation inhibited the impacts of APOC1 deletion on the malignant behavior of osteosarcoma cells. APOC1 silencing-induced oxidative phosphorylation elevation and Warburg effect decrease were partially restored by MTCH2 upregulation. In sum, APOC1 promoted progression of osteosarcoma by binding to MTCH2, suggesting that targeting the APOC1/MTCH2 axis may be a potential treatment of osteosarcoma.

Glioblastoma poses an inevitable threat to patients despite aggressive therapy regimes. It displays a great level of molecular heterogeneity and numerous substitutions in several genes have been documented. Next-generation sequencing techniques have identified various molecular signatures that have led to a better understanding of the molecular pathogenesis of glioblastoma. In this limited study, we sought to identify genetic variants in a small number of rare patients with aggressive glioblastoma.

Five tumor tissue samples were isolated from four patients with rapidly growing glioblastoma. Genomic DNA was isolated and whole exome sequencing was used to study protein-coding regions. Generated FASTQ files were analyzed and variants were called for each sample. Variants were prioritized with different approaches and functional annotation was applied for the detrimental variants.

A total of 49,780 somatic variants were identified in the five glioblastoma samples studied, with the majority as missense substitutions. The top ten genes with the highest number of substitutions were MUC3A, MUC4, MUC6, OR4C5, PDE4DIP, AHNAK2, OR4C3, ZNF806, TTN, and RP1L1. Notably, variant prioritization after annotation indicated that the MTCH2 (Chr11: 47647265 A>G) gene sequence change was putative deleterious in all of the aggressive tumor samples.

The MTCH2 (Chr11: 47647265 A>G) gene substitution was identified as putative deleterious in highly aggressive glioblastomas, which merits further investigation. Moreover, a high tumor mutation burden was observed, with a signature of the highest substitutions in MUC3A, MUC4, MUC6, OR4C5, PDE4DIP, AHNAK2, OR4C3, ZNF806, TTN, and RP1L1 genes. The findings provide critical, initial data for the further rational design of genetic screening and diagnostic approaches against aggressive glioblastoma.