Microsatellite stable (MSS) colorectal cancer (CRC) is often characterized as a "cold" tumor, exhibiting minimal responsiveness to monotherapy with PD-1 antibodies. The underlying mechanisms of this intrinsic unresponsiveness to immunotherapy have been elusive. Here, we report that cathepsin D (CTSD) is highly expressed in MSS CRC, significantly contributing to its resistance to immunotherapy. Specifically, CTSD facilitates immune evasion by shielding cancer cells from cytotoxic T-cell-mediated killing. Mechanistically, as a protease, CTSD interacts with the α2 domain of the major histocompatibility complex class I (MHC-I) molecule via its catalytic domain's light chain, promoting the degradation of MHC-I through lysosomal pathways and disrupting the recycling of MHC-I to the cell surface. Notably, deletion or pharmacological inhibition of CTSD with pepstatin A prevents this immune evasion and enhances the efficacy of anti-PD-1 antibodies. Collectively, these findings highlight the role of CTSD in immune evasion and provide a compelling rationale for the development of a novel combination therapy involving CTSD inhibition and anti-PD-1 immunotherapy in CRC.
DEPDC1 supports tumor growth, migration and metastases formation. To investigate what is the gene expression network regulated by DEPDC1, we silenced its expression in MDA-MB-231 Triple Negative Breast Cancer (TNBC) cell line. We then performed gene expression profiling analysis using data obtained from RNA-seq of MDA-MB 231.
our study reconstructs a comprehensive communication network for human preimplantation lineages and integrates it with downstream gene regulatory networks, thus offering vital insights into lineage specification and cell fate regulation during human embryonic development.
Purpose: To understand the molecular mechanism and severe phenotype caused by the mutation of Nup50c, we performed the whole genome transcriptome analysis on 9-day-old seedlings of WT and nup50c. Conclusions: Nup50c regulates stress-related gene expression
BUB1 is a nuclear serine/threonine protein kinase and a vital spindle assembly checkpoint (SAC) complex member responsible for proper chromosome segregation before mitosis. Here we report that BUB1 plays an unexpected cytoplasmic role in restraining DNA damage-induced accumulation of cytoplasmic dsRNA and ensuing immune response. We showed that tumors deficient in BUB1 were sensitive to radiotherapy in a CD8+T-cell-dependent manner. Furthermore, we discovered increased immune cell infiltration accompanied by elevated type I interferon production from irradiated BUB1-deficient cells, caused by enhanced cytoplasmic dsRNA accumulation and activation of the MDA5/MAVS/IRF7 dsRNA-sensing pathway. Mechanistically, we discovered that after exposure to ionizing radiation, BUB1 underwent a robust nucleus-to-cytoplasm migration, where it bound and phosphorylated the polyA-binding protein PABPC1, which was degraded together with its associated mRNAs stored in the stress granules, thereby preventing dsRNA accumulation and activation of the innate immune response. Our study, therefore, reveals a novel biological role for BUB1 in suppressing DNA-damage-induced cytoplasmic dsRNA accumulation/viral mimicry and provides a rationale for inhibiting BUB1 to enhance cytotoxic cancer therapy immunologically.
BUB1 is a nuclear serine/threonine protein kinase and a vital spindle assembly checkpoint (SAC) complex member responsible for proper chromosome segregation before mitosis. Here we report that BUB1 plays an unexpected cytoplasmic role in restraining DNA damage-induced accumulation of cytoplasmic dsRNA and ensuing immune response. We showed that tumors deficient in BUB1 were sensitive to radiotherapy in a CD8+T-cell-dependent manner. Furthermore, we discovered increased immune cell infiltration accompanied by elevated type I interferon production from irradiated BUB1-deficient cells, caused by enhanced cytoplasmic dsRNA accumulation and activation of the MDA5/MAVS/IRF7 dsRNA-sensing pathway. Mechanistically, we discovered that after exposure to ionizing radiation, BUB1 underwent a robust nucleus-to-cytoplasm migration, where it bound and phosphorylated the polyA-binding protein PABPC1, which was degraded together with its associated mRNAs stored in the stress granules, thereby preventing dsRNA accumulation and activation of the innate immune response. Our study, therefore, reveals a novel biological role for BUB1 in suppressing DNA-damage-induced cytoplasmic dsRNA accumulation/viral mimicry and provides a rationale for inhibiting BUB1 to enhance cytotoxic cancer therapy immunologically.
Topoisomerase I (Top1) is a classical drug target for anticancer therapy, but its role in immune signaling in cancer cells remain unclear. Here, we aimed to explore the possible role and mechanism of Irinotecan (CPT-11) in anti-tumor immunity.
To examine differential effect of the mutation of Arabidopsis dof1.7 on the gene expressions, we performed microarray analysis using whole seedlings of wild-type and dof1.7-KO mutant.
Mutations in STAMBP have been well-established to cause congenital human microcephaly-capillary malformation (MIC-CAP) syndrome, a rare genetic disorder characterized by global developmental delay, severe microcephaly, capillary malformations, etc.We report here that STAMBP is dispensable for the pluripotency maintenance or neural differentiation of hESCs. However, neural progenitor cells (NPCs) derived from STAMBP-deficient hESCs fail to be long-term maintained/expanded in vitro. We identified the anti-apoptotic protein CFLAR is down-regulated in those affected NPCs and ectopic expression of CFLAR rescues NPC defects induced by STMABP-deficiency.
For patients with advanced or metastatic Hepatocellular carcinoma (HCC) who are not suitable for surgical resection, systemic therapy has been considered to be the standard treatment. In recent years, a small subset of patients with unresectable HCC have been benefit from tyrosine kinase inhibitors (TKIs), and the overall survival time of these patients is significantly increased. However, all responders ultimately develop resistance to TKI treatment. The tripartite motif (TRIM) family member TRIM15 acts as an E3 ligase to mediate the polyubiquitination of substrates in cells. However, the biological role of TRIM15 in HCC is still an enigma. In our study, our results demonstrated that TRIM15 was abnormally upregulated in liver cancer cells after treated with TKIs and that this upregulation of TRIM15 contributed to TKI resistance in liver cancer cells. Then, we demonstrated that the upregulation of TRIM15 after TKI treatment was mediated by the AKT/FOXO1 axis. Moreover, we demonstrated that TRIM15 induced the nuclear translocation of LASP1 by mediating its K63-linked polyubiquitination, which modulated sensitivity to TKIs by increasing the phosphorylation of AKT and the expression of Snail in liver cancer cells. Collectively, we identified a novel AKT/FOXO1/TRIM15/LASP1 loop in cells, which provided potential candidates for overcoming TKI resistance in HCC.