Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We discovered that an inverse relationship exists in the expression of ras/c-myc and ribosomal protein RPS2 with pre-let-7a-1/let-7a/let-7f miRNA and prostate tumor cell malignancy. Nonmalignant IBC-10a cells expressed low levels of ras/RPS2 and elevated pre-let-7a-1/let-7a/let-7f miRNA, whereas the reverse occurred in malignant PCa-20a and PC-3ML cells. Stable transfection of IBC-10a cells with pBABE.ras and pBABE.RPS2 induced ras, c-myc, and RPS2 expression, whereas the levels of let-7a/let-7f miRNA dropped to near zero. Conversely, in pBABE.pre-let-7a-1 transfected PCa-20a and PC-3ML clones, let-7a/let-7f increased whereas ras, RPS2, and c-myc dropped greater than 5-fold. Electrophoretic mobility shift assays, antibody "supershift" assays and immunoprecipitation assays revealed that RPS2 specifically binds pre-let-7a-1 to block RNA processing. Immunoflourescent studies and Northern blots confirmed that RPS2 complexes with pre-let-7a-1 (i.e., in episomal structures) to block processing to let-7a/let-7f, indicating RPS2 may prevent let-7a miRNA expression to indirectly promote oncogene expression. Functional studies further showed that the colony-forming ability (CFA) and invasive activities of IBC-10a cells were significantly enhanced in pBABE-ras.IBC-10a and pBABE-RPS2-IBC-10a clones. Conversely, with the "knockdown" of ras and RPS2 in malignant PC-3ML cells (i.e., in pLKO.TRC.shRNA.ras.PC3-ML, pLKO.TRC.shRNA.RPS2.PC-3ML transfected cells), there was both a loss of these functions and a loss of tumorigenesis in SCID mice. Likewise, with the overexpression of let-7a/let-7f in pBABE.pre-let-7a-1.PC-3ML clones (and PCa-20a clones), CFAs, invasive activities in vitro, and tumorigenesis in vivo were significantly reduced. These results show for the first time that RPS2 blocks pre-let-7a-1 processing to enable ras and c-myc expression and the transformation of primary tumor cells.
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PMID:Role of ribosomal protein RPS2 in controlling let-7a expression in human prostate cancer. 2243 56

The Akt/mammalian target of rapamycin (mTOR) pathway plays important roles in modulating cellular function in response to extracellular signals such as growth factors and cytokines. The Akt/mTOR signaling pathway is activated in certain kinds of sarcomas. Myxofibrosarcoma is a soft tissue sarcoma, characterized by abundant myxoid stroma and frequent local recurrence. Here, we conducted a large-scale examination of the clinicopathological and activation statuses of the Akt/mTOR pathways in myxofibrosarcoma. The phosphorylation status of Akt, mTOR, S6 ribosomal protein, and the eukaryotic translation initiation factor 4E-binding protein, and mitogen-activated protein kinase were assessed by immunohistochemistry in 101 formalin-fixed, paraffin-embedded samples, including 68 primary tumors in myxofibrosarcoma. Immunohistochemical expressions were confirmed by Western blotting with 20 frozen samples, which were paired with normal tissue samples. PIK3CA and AKT1 gene mutations were also analyzed using 12 primary tumor frozen samples. Immunohistochemically, phosphorylations of Akt, mTOR, S6 ribosomal protein, 4E-binding protein, and mitogen-activated protein kinase 1/2 were observed in 64.7%, 45.6%, 42.6%, 63.2%, and 64.7% of samples. Phosphorylated Akt/mTOR pathway proteins were correlated with one another and were also correlated with the phosphorylation of these proteins in the concordant recurrent tumors. Immunoblotting showed a high degree of phosphorylation in tumor samples, compared with that in normal tissue samples. Activation of the Akt/mTOR pathway was correlated with histologic grade and tumor progression. Mutational analysis failed to reveal any PIK3CA or AKT1 mutations around the hot spots. Activation of the Akt/mTOR pathway was associated with histologic malignancy and tumor progression in primary and recurrent myxofibrosarcoma.
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PMID:Activation of the Akt/mammalian target of rapamycin pathway in myxofibrosarcomas. 2474 2

mTOR inhibitors are used to treat renal cell carcinoma (RCC). Treatment response is variable and appears to correlate with genetic alterations that activate mTOR signaling. Recently, everolimus was suggested to be more effective than sunitinib in chromophobe RCC (chRCC), a tumor with frequent mTOR pathway defects. This report presents the genomic and functional characterization of a metastatic chRCC that showed complete response at metastatic sites and 80% reduction in primary tumor size upon temsirolimus treatment. After surgery, the patient remained disease-free for 8 years after temsirolimus therapy. Whole-exome sequencing (WES) revealed 2 somatic variants in TSC2, a critical negative regulator of mTOR: a splicing defect (c.5069-1G>C) and a novel missense variant [c.3200_3201delinsAA; p.(V1067E)]. In vitro functional assessment demonstrated that the V1067E substitution disrupted TSC2 function. Immunohistochemistry in the tumor tissues revealed increased phosphorylated S6 ribosomal protein, indicating mTOR pathway activation. In conclusion, WES revealed TSC2 inactivation as the likely mechanism for this extraordinary response to temsirolimus. These findings support high efficacy of mTOR inhibitors in a subset of patients with chRCC and propose sequencing of mTOR pathway genes to help guide therapy.
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PMID:Biallelic TSC2 Mutations in a Patient With Chromophobe Renal Cell Carcinoma Showing Extraordinary Response to Temsirolimus. 2963 54

Dual oxidase 2 (DUOX2) is an important regulatory protein in the organic process of thyroid hormone iodine. Mounting evidence suggests that DUOX2 plays a crucial role in the occurrence and development of cancers. However, the function and mechanism of DUOX2 in colorectal cancer (CRC) has not been fully clarified. In the present study, the relationship between the expression of DUOX2 and the clinicopathological features and prognosis of CRC patients was analyzed. Furthermore, the effects of DUOX2 on proliferation and invasion in vitro and in vivo were examined. DUOX2-associated proteins were identified by immunoprecipitation (IP). Next-generation sequencing (NGS) detection was performed to illustrate the mechanism of DUOX2 in CRC cells. It was found that the expression levels of DUOX2 in metastatic sites were significantly higher than those in primary tumor tissues, and this was demonstrated to be associated with poor prognosis. The knockdown of DUOX2 inhibited the invasion and migration of CRC cells. Furthermore, DUOX2 regulated the stability of ribosomal protein uL3 (RPL3) by affecting the ubiquitination status of RPL3, and the invasion and migration ability of DUOX2 can be reversed by the overexpression of RPL3. The downregulation of DUOX2 can affect the expression level of a large number of genes, and a number of these are enriched in the PI3K-AKT pathway. Some of the changes caused by DUOX2 can be reversed by RPL3. In summary, DUOX2 exhibits a significantly higher expression in CRC tumor samples, and facilitates the invasion and metastasis ability of CRC cells by interacting with RPL3.
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PMID:DUOX2 promotes the progression of colorectal cancer cells by regulating the AKT pathway and interacting with RPL3. 3253 Oct 52