Nuclear accumulation of ADAMTS1 zymogen: A novel mechanism promoting chemoresistance and metastasis in breast cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1312462 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Chemoresistance and metastasis are the primary causes of mortality in patients with breast cancer. Here, we demonstrated that the metalloproteinase ADAMTS1 is upregulated in chemotherapy-treated and metastatic breast cancer samples. Mechanistically, the zymogen form of ADAMTS1 undergoes nuclear translocation via importin-dependent transport, where it cooperates with the SWI/SNF complex to activate a set of genes, including TBK1, STING, TRAF6, and MARCHF2, leading to STING ubiquitination and the non-classical cGAS-STING-NF-kB signaling activation, which in turn promotes chemoresistance and metastasis. Notably, long-term chemotherapy establishes a self-reinforcing loop by: (i) NF-kB/p65-mediated transcriptional induction of ADAMTS1, and (ii) MARCHF2-dependent ubiquitin-proteasomal degradation of FURIN, the protease responsible for ADAMTS1 maturation. This dual regulation results in nuclear accumulation of catalytically inactive ADAMTS1 zymogen. Clinical analyses have shown that high ADAMTS1 expression combined with low FURIN expression is strongly associated with poor patient prognosis. These results reveal a key role for the zymogen ADAMTS1 in inducing tumor chemoresistance and metastasis in response to long-term chemotherapy stimulation, supporting the use of its inhibitor melatonin as a therapeutic strategy in combination with chemotherapy for patients with breast cancer.
2025-09-03 | GSE306824 | GEO
Project description:Chemoresistance and metastasis are the primary causes of mortality in patients with breast cancer. Here, we demonstrated that the metalloproteinase ADAMTS1 is upregulated in chemotherapy-treated and metastatic breast cancer samples. Mechanistically, the zymogen form of ADAMTS1 undergoes nuclear translocation via importin-dependent transport, where it cooperates with the SWI/SNF complex to activate a set of genes, including TBK1, STING, TRAF6, and MARCHF2, leading to STING ubiquitination and the non-classical cGAS-STING-NF-kB signaling activation, which in turn promotes chemoresistance and metastasis. Notably, long-term chemotherapy establishes a self-reinforcing loop by: (i) NF-kB/p65-mediated transcriptional induction of ADAMTS1, and (ii) MARCHF2-dependent ubiquitin-proteasomal degradation of FURIN, the protease responsible for ADAMTS1 maturation. This dual regulation results in nuclear accumulation of catalytically inactive ADAMTS1 zymogen. Clinical analyses have shown that high ADAMTS1 expression combined with low FURIN expression is strongly associated with poor patient prognosis. These results reveal a key role for the zymogen ADAMTS1 in inducing tumor chemoresistance and metastasis in response to long-term chemotherapy stimulation, supporting the use of its inhibitor melatonin as a therapeutic strategy in combination with chemotherapy for patients with breast cancer.
2025-09-04 | GSE307248 | GEO
Project description:Nuclear accumulation of ADAMTS1 zymogen: A novel mechanism promoting chemoresistance and metastasis in breast cancer [RNA-Seq]
| PRJNA1314843 | ENA
Project description:Phosphorylated TLR3 nuclear translocation in cancer cell promotes metastasis and chemoresistance
2025-06-07 | PXD064767 |
Project description:The development of therapeutic resistance and metastatic dissemination takes place in 20-30% patients with nasopharyngeal carcinoma (NPC), resulting in poor survival. Hence, a better understanding of the underlying molecular mechanisms will help improve clinical outcome. We have identified a novel circRNA, circIPO7, as a promoter of metastasis and cisplatin chemoresistance in NPC cells. Expression profiling and Genome binding/occupancy profiling by high throughput sequencing were performed to explore the underlying molecular mechanisms.
2022-07-26 | GSE189459 | GEO
Project description:Phosphorylated TLR3 nuclear translocation in cancer cell promotes metastasis and chemoresistance
| PRJNA1272840 | ENA
Project description:This experiment is designed to screen miRNAs that are deregulated during chemoresistance-associated metastasis of lung cancer cells. Chemoresistant metastatic in vivo tumor model of A549-luc-Vector cells was established after four rounds of cisplatin (CDDP) treatments compared to corresponding control solvent treatments. Upon examining profiles of miRNA expression differential between tumor-derived cultured cells from the Ctrl-4th and CDDP-4th treatments, most markedly upregulated and downregulated miRNAs in chemoresistant, metastatic A549-luc-CDDP-4th cells were identified. In order to establish a chemoresistant in vivo tumor model, after inoculation of A549-luc-Vector cells, cisplatin (CDDP) or control solvent was intraperitoneally (i.p.) injected six rounds in a two-week period and cells were isolated from corresponding resultant tumors, cultured and re-transplanted into syngeneic mice to receive the next round of treatment. In our experimental model, human lung cancer xenografts developed chemoresistance in the third round of CDDP treatment (CDDP-3rd) and chemoresistance-associated metastases following the fourth round of treatment. Tumor-derived cultured cells from Ctrl-4th and CDDP (cisplatin)-4th treatment were subjected to miRNA array (Agilent-031181 human miRNA (8*60k) V16.0) analysis, with two biological replications for each treatment.
2015-04-10 | E-GEOD-67727 | biostudies-arrayexpress
Project description:Aberrant expression and subcellular location of innate sensors in cancer cells, such as Toll-like receptors (TLRs), correlates with pro-tumoral inflammation and cancer progression, but the mechanism is still largely unknown. Deciphering the proinflammatory mediators in tumor microenvironment will contribute to the development of cancer therapeutics. By using immunohistochemistry in pancreatic ductal adenocarcinoma (PDAC) and multiple other cancer samples, here we found that cancer cell TLR3, a well-known cytoplasmic dsRNA sensor, translocated to the nucleus especially upon chemotherapy stress. Nuclear TLR3 increased the invasive and proliferative properties, and inhibited chemotherapy-induced apoptosis of cancer cells in vitro. Meanwhile, mice bearing cancer cells with nuclear TLR3 exhibited increased liver metastasis and shortened survival. Mechanistically, phosphokinase JAK1 was responsible for TLR3 phosphorylation at S155 to induce its nuclear translocation in cooperation with a nuclear transport factor importin α5. Chemotherapeutic stress induced the aberrant aggregation of dsRNA in the nucleus, which potentially contributed to nuclear TLR3 activation. Then nuclear TLR3 recruited protein arginine methyltransferase 5 (PRMT5) and bound to c-Myc to promote symmetrical dimethylation and multimerization of c-Myc, resulting in the activation of c-Myc downstream target genes and pro-tumoral signaling pathways. Accordingly, high levels of cancer cell nuclear TLR3 in clinical samples predicted patients’ worse prognosis with shorter disease-free survival, overall survival and poor response to neoadjuvant chemotherapy. Therefore, the identification of nuclear TLR3 provides new insight into non-classical functions of innate immune sensors in cancer, and JAK1/TLR3/PRMT5/c-Myc axis may sever as a new prognostic indicator and potential therapeutic target to overcome chemoresistance.
2025-06-30 | GSE299145 | GEO
Project description:CircIPO7 Promotes Nasopharyngeal Carcinoma Metastasis and Cisplatin Chemoresistance by Regulating YBX1 Nuclear Localization
| PRJNA783043 | ENA
Project description:AKR1C1, a member of the AKR1C family, has been identified as a key player in cancer progression, promoting cancer cell proliferation and inhibiting apoptosis. Here, we identified AKR1C1 as a potential crucial gene significantly associated with oxaliplatin (OXA) sensitivity and unfavorable clinical outcomes through the transcriptome analysis of OXA-sensitive and -resistant colorectal cancer cell lines. Both in vitro and in vivo, AKR1C1 promotes cancer cell proliferation and confers OXA chemoresistance in colorectal cancer cells. Mechanistically, AKR1C1 interacts with and activates STAT3 and increases glutathione (GSH) levels, resulting in chemoresistance in colorectal cancer cells. Moreover, pharmacologic inhibition of AKR1C1 with alantolactone restores the sensitivity of resistant cell lines to OXA and the combined treatment of alantolactone with OXA exhibits superior antitumor effects in mouse xenografts. Collectively, the present study offers compelling evidence that AKR1C1 expression confers resistance to OXA in colorectal cancer, providing a promising strategy to circumvent chemoresistance.
2024-12-11 | GSE235026 | GEO