We are analyzing https://link.springer.com/article/10.1186/s12943-019-1070-7.

Title:
Transcriptional inhibition by CDK7/9 inhibitor SNS-032 abrogates oncogene addiction and reduces liver metastasis in uveal melanoma | Molecular Cancer
Description:
Background Life of patients with uveal melanoma (UM) is largely threatened by liver metastasis. Little is known about the drivers of liver organotropic metastasis in UM. The elevated activity of transcription of oncogenes is presumably to drive aspects of tumors. We hypothesized that inhibition of transcription by cyclin-dependent kinase 7/9 (CDK7/9) inhibitor SNS-032 diminished liver metastasis by abrogating the putative oncogenes in charge of colonization, stemness, cell motility of UM cells in host liver microenvironment. Methods The effects of SNS-032 on the expression of the relevant oncogenes were examined by qRT-PCR and Western blotting analysis. Proliferative activity, frequency of CSCs and liver metastasis were evaluated by using NOD-SCID mouse xenograft model and NOG mouse model, respectively. Results The results showed that CDK7/9 were highly expressed in UM cells, and SNS-032 significantly suppressed the cellular proliferation, induced apoptosis, and inhibited the outgrowth of xenografted UM cells and PDX tumors in NOD-SCID mice, repressed the cancer stem-like cell (CSC) properties through transcriptional inhibition of stemness-related protein Krüppel-like factor 4 (KLF4), inhibited the invasive phonotypes of UM cells through matrix metalloproteinase 9 (MMP9). Mechanistically, SNS-032 repressed the c-Myc-dependent transcription of RhoA gene, and thereby lowered the RhoA GTPase activity and actin polymerization, and subsequently inhibited cell motility and liver metastasis. Conclusions In conclusion, we validate a set of transcription factors which confer metastatic traits (e.g., KLF4 for CSCs, c-Myc for cell motility) in UM cells. Our results identify SNS-032 as a promising therapeutic agent, and warrant a clinical trial in patients with metastatic UM.
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Keywords {🔍}

sns, cells, pubmed, article, cancer, cell, fig, rhoa, google, scholar, yap, metastasis, cas, analysis, klf, transcription, melanoma, assay, metastatic, expression, results, treatment, levels, cdk, uveal, tumor, mice, mmp, liver, patients, western, protein, test, treated, cscs, inhibited, growth, invasion, blot, showed, examined, apoptosis, migration, mel, omm, decreased, survivin, gene, central, tumors,

Topics {✒️}

real-time quantitative rt-pcr sun yat-sen university annexin v-fitc/pi rhoa-rock-limk1/2-cofilin pathway patient-derived xenograft model triple-negative breast cancer zhongshan ophthalmic center um patient-derived xenograft article download pdf cancer cell biology wound-healing scratch assay trio-rho/rac signaling stemness-related transcription factors hypoxia-induced wsb1 promotes myc-dependent transcriptional upregulation active gtp-bound forms stemness-related proteins klf4 apoptosis-related proteins expression xenograft nod-scid mice c-myc-dependent transcription paraffin-embedded tumor xenografts circulating tumour cells bcr-abl oncogene addiction author information authors active gtp-bound form male nod-scid mice cdk7-dependent transcriptional addiction abrogated c-myc addiction sns-032 dose-dependently inhibited mitogen-activated protein kinase mutant gαq/11-driven tumorigenesis sns-032-mediated growth inhibition supplementary figures s1-f3 yap-dependent gene transcription cyclin-dependent kinase 7/9 anchorage-independent colony growth eliminates cancer stem apoptosis-related proteins apoptosis-related protein survivin dmem/f12 medium supplemented full access institutional animal care sns-032-induced csc elimination fda-approved standard therapy original author stemness-related proteins qrt-pcr assay showed stemness-related protein krüppel c-myc partially rescued verteporfin induces apoptosis

Questions {❓}

Regulation of the cytoskeleton: an oncogenic function for CDK inhibitors?
Treatment of uveal melanoma: where are we now?

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         headline:Transcriptional inhibition by CDK7/9 inhibitor SNS-032 abrogates oncogene addiction and reduces liver metastasis in uveal melanoma
         description:Life of patients with uveal melanoma (UM) is largely threatened by liver metastasis. Little is known about the drivers of liver organotropic metastasis in UM. The elevated activity of transcription of oncogenes is presumably to drive aspects of tumors. We hypothesized that inhibition of transcription by cyclin-dependent kinase 7/9 (CDK7/9) inhibitor SNS-032 diminished liver metastasis by abrogating the putative oncogenes in charge of colonization, stemness, cell motility of UM cells in host liver microenvironment. The effects of SNS-032 on the expression of the relevant oncogenes were examined by qRT-PCR and Western blotting analysis. Proliferative activity, frequency of CSCs and liver metastasis were evaluated by using NOD-SCID mouse xenograft model and NOG mouse model, respectively. The results showed that CDK7/9 were highly expressed in UM cells, and SNS-032 significantly suppressed the cellular proliferation, induced apoptosis, and inhibited the outgrowth of xenografted UM cells and PDX tumors in NOD-SCID mice, repressed the cancer stem-like cell (CSC) properties through transcriptional inhibition of stemness-related protein Krüppel-like factor 4 (KLF4), inhibited the invasive phonotypes of UM cells through matrix metalloproteinase 9 (MMP9). Mechanistically, SNS-032 repressed the c-Myc-dependent transcription of RhoA gene, and thereby lowered the RhoA GTPase activity and actin polymerization, and subsequently inhibited cell motility and liver metastasis. In conclusion, we validate a set of transcription factors which confer metastatic traits (e.g., KLF4 for CSCs, c-Myc for cell motility) in UM cells. Our results identify SNS-032 as a promising therapeutic agent, and warrant a clinical trial in patients with metastatic UM.
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         dateModified:2021-10-16T00:00:00Z
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      headline:Transcriptional inhibition by CDK7/9 inhibitor SNS-032 abrogates oncogene addiction and reduces liver metastasis in uveal melanoma
      description:Life of patients with uveal melanoma (UM) is largely threatened by liver metastasis. Little is known about the drivers of liver organotropic metastasis in UM. The elevated activity of transcription of oncogenes is presumably to drive aspects of tumors. We hypothesized that inhibition of transcription by cyclin-dependent kinase 7/9 (CDK7/9) inhibitor SNS-032 diminished liver metastasis by abrogating the putative oncogenes in charge of colonization, stemness, cell motility of UM cells in host liver microenvironment. The effects of SNS-032 on the expression of the relevant oncogenes were examined by qRT-PCR and Western blotting analysis. Proliferative activity, frequency of CSCs and liver metastasis were evaluated by using NOD-SCID mouse xenograft model and NOG mouse model, respectively. The results showed that CDK7/9 were highly expressed in UM cells, and SNS-032 significantly suppressed the cellular proliferation, induced apoptosis, and inhibited the outgrowth of xenografted UM cells and PDX tumors in NOD-SCID mice, repressed the cancer stem-like cell (CSC) properties through transcriptional inhibition of stemness-related protein Krüppel-like factor 4 (KLF4), inhibited the invasive phonotypes of UM cells through matrix metalloproteinase 9 (MMP9). Mechanistically, SNS-032 repressed the c-Myc-dependent transcription of RhoA gene, and thereby lowered the RhoA GTPase activity and actin polymerization, and subsequently inhibited cell motility and liver metastasis. In conclusion, we validate a set of transcription factors which confer metastatic traits (e.g., KLF4 for CSCs, c-Myc for cell motility) in UM cells. Our results identify SNS-032 as a promising therapeutic agent, and warrant a clinical trial in patients with metastatic UM.
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      dateModified:2021-10-16T00:00:00Z
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         Cell motility
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         Liver metastasis
         Cancer Research
         Oncology
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