Matrin-3 acts as a potential biomarker and promotes hepatocellular carcinoma progression by interacting with cell cycle-regulating genes.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The oncogenic role of Matrin-3 (MATR3), an a nuclear matrix protein, in HCC remains largely unknown. Here, we document the biological function of MATR3 in HCC based on integrated bioinformatics analysis and functional studies. According to the TCGA database, MATR3 expression was found to be positively correlated with clinicopathological characteristics in HCC. The receiver operating characteristic (ROC) curve and Kaplan-Meier (KM) curve displayed the diagnostic and prognostic potentials of MATR3 in HCC patients, respectively. Pathway enrichment analysis represented the enrichment of MATR3 in various molecular pathways, including the regulation of the cell cycle. Functional assays in HCC cell lines showed reduced proliferation of cells with stable silencing of MATR3. At the same time, the suppressive effects of MATR3 depletion on HCC development were verified by xenograft tumor experiments. Moreover, MATR3 repression also resulted in cell cycle arrest by modulating the expression of cell cycle-associated genes. In addition, the interaction of MATR3 with cell cycle-regulating factors in HCC cells was further corroborated with co-immunoprecipitation and mass spectrometry (Co-IP/MS). Furthermore, CIBERSORT and TIMER analyses showed an association between MATR3 and immune infiltration in HCC. In general, this study highlights the novel oncogenic function of MATR3 in HCC, which could comprehensively address how aberrant changes in the cell cycle promote HCC development. MATR3 might serve as a prognostic predictor and therapeutic target for HCC patients.

CCR9 overexpression promotes T-ALL progression by enhancing cholesterol biosynthesis.

Introduction: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of the lymphoid progenitor cells, contributing to ∼ 20% of the total ALL cases, with a higher prevalence in adults than children. Despite the important role of human T-ALL cell lines in understanding the pathobiology of the disease, a detailed comparison of the tumorigenic potentials of two commonly used T-ALL cell lines, MOLT4 and JURKAT cells, is still lacking. Methodology: In the present study, NOD-Prkdc scid IL2rgd ull (NTG) mice were intravenously injected with MOLT4, JURKAT cells, and PBS as a control. The leukemiac cell homing/infiltration into the bone marrow, blood, liver and spleen was investigated for bioluminescence imaging, flow cytometry, and immunohistochemistry staining. Gene expression profiling of the two cell lines was performed via RNA-seq to identify the differentially expressed genes (DEGs). CCR9 identified as a DEG, was further screened for its role in invasion and metastasis in both cell lines in vitro. Moreover, a JURKAT cell line with overexpressed CCR9 (Jurkat-OeCCR9) was investigated for T-ALL formation in the NTG mice as compared to the GFP control. Jurkat-OeCCR9 cells were then subjected to transcriptome analysis to identify the genes and pathways associated with the upregulation of CCR9 leading to enhanced tumirogenesis. The DEGs of the CCR9-associated upregulation were validated both at mRNA and protein levels. Simvastatin was used to assess the effect of cholesterol biosynthesis inhibition on the aggressiveness of T-ALL cells. Results: Comparison of the leukemogenic potentials of the two T-ALL cell lines showed the relatively higher leukemogenic potential of MOLT4 cells, characterized by their enhanced tissue infiltration in NOD-PrkdcscidIL2rgdull (NTG) mice. Transcriptmoe analysis of the two cell lines revealed numerous DEGs, including CCR9, enriched in vital signaling pathways associated with growth and proliferation. Notably, the upregulation of CCR9 also promoted the tissue infiltration of JURKAT cells in vitro and in NTG mice. Transcriptome analysis revealed that CCR9 overexpression facilitated cholesterol production by upregulating the expression of the transcriptional factor SREBF2, and the downstream genes: MSMO1, MVD, HMGCS1, and HMGCR, which was then corroborated at the protein levels. Notably, simvastatin treatment reduced the migration of the CCR9-overexpressing JURKAT cells, suggesting the importance of cholesterol in T-ALL progression. Conclusions: This study highlights the distinct tumorigenic potentials of two T-ALL cell lines and reveals CCR9-regulated enhanced cholesterol biosynthesis in T-ALL.

LncRNA15691 promotes T-ALL infiltration by upregulating CCR9 via increased MATR3 stability.

Our previous studies demonstrated that CCR9 plays an important role in several aspects of T-cell acute lymphoblastic leukemia progression and that CCR9 is a potential therapeutic target. However, the underlying mechanism that regulates CCR9 expression remains incompletely understood. In this study, bioinformatics analysis and validation in clinical samples revealed the lncRNA15691 to be positively correlated with CCR9 mRNA expression and significantly upregulated in T-cell acute lymphoblastic leukemia samples and CCR9high T-cell acute lymphoblastic leukemia cell lines. LncRNA15691, a previously uncharacterized lncRNA, was found to be located in both the cytoplasm and the nucleus via fluorescence in situ hybridization assay. In addition, lncRNA15691 upregulated the expression of CCR9 and was involved in T-cell acute lymphoblastic leukemia cell invasion. In vivo experiments showed that lncRNA15691 promoted leukemia cell homing/infiltration into the bone marrow, blood, and spleen, whereas the CCR9 ligand, CCL25, augmented the extramedullary infiltration of CCR9low leukemia cells overexpressing lncRNA15691 into blood, spleen, and liver. Subsequently, RNA protein pull-down assays, coupled with liquid chromatography-tandem mass spectrometry, were used to uncover potential lncRNA15691-interacting proteins, which were then validated by RNA immunoprecipitation. These mechanistic studies revealed that lncRNA15691 upregulated CCR9 expression via directly binding to and stabilizing MATR3 by inhibiting its nuclear degradation mediated by PKA. Collectively, our study revealed a novel mechanism of regulating CCR9 expression and implicated lncRNA15691 as a potential novel biomarker for T-cell acute lymphoblastic leukemia infiltration.

TTYH3, a potential prognosis biomarker associated with immune infiltration and immunotherapy response in lung cancer.

PURPOSE: The recognition of new diagnostic and prognostic biological markers for lung cancer is an essential and eager study. It's shown that ion channels play important roles in regulating various cellular processes and have been suggested to be associated with patient survival. However, tweety family member 3 (TTYH3), as a maxi-Cl- channel, its role in lung cancer remains elusive. METHODS: The expression, diagnostic and prognostic efficacy of TTYH3 were analyzed by public databases and clinical samples. Cell functional experiments were used to explore the effects of TTYH3 on cell viability. GO and KEGG enrichment analysis revealed underlying pathways that TTYH3 and its co-expressed genes were enriched in. TIMER, TIDE and R language analyses were used to detect the correlation between TTYH3 and immune infiltration cell and immunotherapy response. RESULTS: TTYH3 was up-regulated in lung cancer tissues compared to normal tissues and possessed a prominent diagnostic and prognostic value. TTYH3 knockdown significantly inhibited the proliferation of lung cancer cells. Enrichment analyses showed that TTYH3 and its co-expressed genes were mainly involved in immune related signaling pathways. Further investigation clarified that TTYH3 had a positive correlation with the infiltration of TAMs, Treg infiltration as well as T cell exhaustion and high TTYH3 expression indicated worse immunotherapy response and shorter survival after immune checkpoint blockade treatment. CONCLUSION: This study not only revealed the diagnostic and prognostic value of TTYH3 but also provided TTYH3-based estimation of immunotherapy response for lung cancer patients, which might provide new strategies like anti-TTYH3 combined with immune therapy for the treatment of lung cancer.

Insulin receptor substrate 1(IRS1) is related with lymph node metastases and prognosis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer-related mortality globally with a high risk of lymph node metastasis (LNM). In this study, weighted gene co-expression network analysis (WGCNA) showed the identification of 10 modules among which the significant module (turquoise), including 1352 genes, was correlated with LNM. A group 52 overlapping differentially expressed genes (DEGs) was identified based on the comparison of turquoise module with GSE23400 and GSE20347 datasets. Using Ctyohubba plugin, we identified 7 hub genes (ACTG2, SORBS1, MYH11, CXCL12, CNN1, IRS1 and CXCL8). IRS1 displayed significant correlation with metastasis. The decreased expression of IRS1 was also a predictor of poor OS of ESCC patients whereas the hub genes namely ACTG2, MYH11, CXCL8, CXCL12, IRS1 and CNN1 were associated with RFS of ESCC patients. These findings suggest that the altered expression of these hub genes are associated with prognosis and thus can be used as potential biomarkers for ESCC. Moreover, immunohistochemical staining and cell functional experiments displayed that the overexpression of IRS1 was negatively associated with metastasis in ESCC. In general, our research revealed several novel genes in ESCC especially the association of IRS1 with LNM in ESCC, which could provide novel insights into the initiation and progression of ESCC.