Hunk as aregulator of TNBC genes involve in tumor immunity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE242859 | GEO | 2024/06/12
REPOSITORIES: GEO
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Project description:Hunk as aregulator of TNBC genes involve in tumor immunity
| PRJNA1015176 | ENA
Project description:We previously identified a novel SNF1/AMPK-related protein kinase, Hunk, from a mammary tumor arising in an MMTV-neu transgenic mouse. The function of this kinase is unknown. Using targeted deletion in mice, we now demonstrate that Hunk is required for the metastasis of c-myc-induced mammary tumors, but is dispensable for normal development. Reconstitution experiments revealed that Hunk is sufficient to restore the metastatic potential of Hunk-deficient tumor cells, as well as defects in migration and invasion, and does so in a manner that requires its kinase activity. Consistent with a role for Hunk in the progression of human cancers, the human homologue of Hunk is overexpressed in aggressive subsets of carcinomas of the ovary, colon, and breast. In addition, a murine gene expression signature that distinguishes Hunk-wild type from Hunk-deficient mammary tumors predicts clinical outcome in women with breast cancer. Together, these findings establish a role for Hunk in metastasis and an in vivo function for this kinase. Hunk-deficient animals were crossed to mice harboring an MMTV-c-myc transgene (Leder et al., 1986). Hunk heterozygous, MMTV-c-myc mice were backcrossed to Hunk heterozygous animals. MMTV-c-myc female animals of each Hunk genotype were mated twice, then monitored twice weekly for mammary tumors. Mice possessing tumors with a maximum diameter of 20 mm were sacrificed and organs were examined at necropsy. Tumor nodules were identified by examination of organs through a Leica Wild MZ8 dissection microscope.
2009-12-31 | E-GEOD-14226 | biostudies-arrayexpress
Project description:We previously identified a novel SNF1/AMPK-related protein kinase, Hunk, from a mammary tumor arising in an MMTV-neu transgenic mouse. The function of this kinase is unknown. Using targeted deletion in mice, we now demonstrate that Hunk is required for the metastasis of c-myc-induced mammary tumors, but is dispensable for normal development. Reconstitution experiments revealed that Hunk is sufficient to restore the metastatic potential of Hunk-deficient tumor cells, as well as defects in migration and invasion, and does so in a manner that requires its kinase activity. Consistent with a role for Hunk in the progression of human cancers, the human homologue of Hunk is overexpressed in aggressive subsets of carcinomas of the ovary, colon, and breast. In addition, a murine gene expression signature that distinguishes Hunk-wild type from Hunk-deficient mammary tumors predicts clinical outcome in women with breast cancer. Together, these findings establish a role for Hunk in metastasis and an in vivo function for this kinase.
2009-12-31 | GSE14226 | GEO
Project description:Hypoxia regulates epithelial to mesenchymal transition (EMT) of cancer cells. However, the mechanism underlying hypoxia-mediated EMT remains largely unknow. Here, utilizing colorectal cell carcinoma (CRC) as a model, we find that HUNK inhibits EMT and suppresses metastasis of CRC cells via its substrate GEF-H1 in a kinase-dependent manner. Mechanistically, HUNK directly phosphorylates GEF-H1 at ser645 site, which activates RhoA and consequently leads to a cascade of phosphorylation of LIMK1/CFL-1, thereby stabilizing F-actin and inhibiting EMT. Moreover, hypoxia suppresses HUNK activity and dephosphorylates GEF-H1 to promote EMT. Clinically, the expression levels of both HUNK and phosphorylation of GEH-H1 ser645 are not only downregulated in CRC tissues with metastasis compared to that without metastasis, but also positively correlated among these tissues. Our findings highlight the importance of hypoxia-regulated HUNK kinase activity and phosphorylation of GEF-H1 in regulation of EMT and metastasis of CRC.
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Project description:TRAIL cytotoxicity is exploited as anti-cancer therapy since many years, however incomplete knowledge is generating many obstacles. Here, we address whether the highly abundant extracellular matrix molecule tenascin-C (TNC) orchestrating an immune suppressive tumor microenvironment and binding TRAIL impacts TRAIL cytotoxicity. We used an immune competent autologous NT193 breast cancer model with a knockdown (KD) of Tnfsf10 (encoding TRAIL) and observed accelerated tumor growth marked by less apoptosis, more proliferation and less myeloid cell infiltration as seen by flow cytometry. Grafting the same Tnfsf10 KD cells into a TNC knockout host showed repressed tumor growth suggesting that TNC is involved in regulating TRAIL functions.
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