Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment.[supplied by OMIM, Apr 2004]
Hook microtubule-tethering protein 3 (HOOK3) is an adaptor protein for microtubule-dependent intracellular vesicle and protein trafficking. In order to assess the role of HOOK3 in prostate cancer we analyzed HOOK3 expression by immunohistochemistry on a TMA containing more than 12,400 prostate cancers. Results were compared to tumor phenotype and PSA recurrence as well as aberrations possibly defining relevant molecular subtypes such as ERG status and deletions of 3p13, 5q21, 6q15 and PTEN. HOOK3 immunostaining was negative in normal luminal cells of prostate epithelium, whereas 53.3% of 10,572 interpretable cancers showed HOOK3 expression, which was considered low in 36.4% and high in 16.9% of cases. High-level HOOK3 expression was linked to advanced tumor stage, high Gleason score, high proliferation index, positive lymph node stage, and PSA recurrence (p<0.0001 each). The prognostic role of HOOK3 expression was independent of established clinico-pathological parameters both in preoperative and postoperative settings. Comparisons with molecular features were performed to draw conclusions on the potential function of HOOK3 in the prostate. A strong association with all examined deletions is consistent with a role of HOOK3 for maintaining genomic integrity by contributing to proper centrosome assembly. Finding HOOK3 expression in 74% of ERG positive but in only 38% of ERG negative cancers (p<0.0001) further suggests functional interactions between these genes. In conclusion, the results of our study identify HOOK3 as a strong candidate prognostic marker with a possible role in maintaining genomic integrity in prostate cancer, which may have potential for inclusion into clinical routine assays.
Small intestine neuroendocrine tumors (SI-NETs) are the most common malignancy of the small bowel. Several clinical trials target PI3K/Akt/mTOR signaling; however, it is unknown whether these or other genes are genetically altered in these tumors. To address the underlying genetics, we analyzed 48 SI-NETs by massively parallel exome sequencing. We detected an average of 0.1 somatic single nucleotide variants (SNVs) per 106 nucleotides (range, 0-0.59), mostly transitions (C>T and A>G), which suggests that SI-NETs are stable cancers. 197 protein-altering somatic SNVs affected a preponderance of cancer genes, including FGFR2, MEN1, HOOK3, EZH2, MLF1, CARD11, VHL, NONO, and SMAD1. Integrative analysis of SNVs and somatic copy number variations identified recurrently altered mechanisms of carcinogenesis: chromatin remodeling, DNA damage, apoptosis, RAS signaling, and axon guidance. Candidate therapeutically relevant alterations were found in 35 patients, including SRC, SMAD family genes, AURKA, EGFR, HSP90, and PDGFR. Mutually exclusive amplification of AKT1 or AKT2 was the most common event in the 16 patients with alterations of PI3K/Akt/mTOR signaling. We conclude that sequencing-based analysis may provide provisional grouping of SI-NETs by therapeutic targets or deregulated pathways.
Yang P, Yan W, Zhang W, et al. [Whole-genome messenger RNA profiling reveals genes involved in malignant progression of glioma]. Zhonghua Yi Xue Za Zhi. 2013; 93(1):5-7 [PubMed] Related Publications
OBJECTIVE: To employ whole-genome messenger RNA profiling to identify the genes involved in malignant progression in glioma. METHODS: The whole genome expressed genes were profiled in 220 glioma patients from the Chinese Glioma Genome Atlas (97 LGGs and 123 HGGs). The differential expressed genes between LGG and HGG were identified by SAM analysis. Microarray data were validated by immunohistochemistry. RESULTS: Among all the detected genes, the genes up-regulated mostly in high-grade glioma were IGFBP-2, CKLF, PTTG1, OSTCL and PTTG2 while those down-regulated mostly SEC31, RRP7B, HOOK3, SNRPN and CSMD3. Validation of IGFBP-2 with immunohistochemical staining showed a good correlation with the microarray data. CONCLUSION: A panel of potential genes of malignant transformation may serve as future targets of gene therapy for glioma.
Voskoboĭnyk LH [Oncogenes RET/PTC and mechanisms of their involvement in thyroid cancerogenesis]. Ukr Biokhim Zh (1999). 2009 Nov-Dec; 81(6):17-25 [PubMed] Related Publications
Papillary thyroid carcinomas are the most common type of thyroid oncopathology, and are rather often associated with the expression of RET/PTC oncogens. The first oncogen RET/PTC1 was isolated more than 20 years ago. Now 13 different forms of RET/PTC are known, and 12 different partner-genes are described, that could be involved in formation of RET/PTC oncogenes. The most common of them are RET/PTC1 and RET/PTC3 forms. The great majority of oncogens RET/PTC, except for two--ELKS-RET and HOOK3-RET, have been founded in radioaction-induced thyroid tumors. There is an opinion that the key role in development of papillary thyroid carcinomas belongs to RET/PTC oncogens. The data about different types of RET/PTC oncogens, factors, that lead to their formation have been described in the present review. Also different mechanisms of activation of transduction pathways and gene's expression in thyroid cells after RET/PTC induction have been presented.
Ciampi R, Giordano TJ, Wikenheiser-Brokamp K, et al. HOOK3-RET: a novel type of RET/PTC rearrangement in papillary thyroid carcinoma. Endocr Relat Cancer. 2007; 14(2):445-52 [PubMed] Related Publications
Chromosomal rearrangements of the RET proto-oncogene (RET/PTC) are the common feature of papillary thyroid carcinoma (PTC). In this study, we report the identification, cloning, and functional characterization of a novel type of RET/PTC rearrangement that results from the fusion of the 3'-portion of RET coding for the tyrosine kinase (TK) domain of the receptor to the 5'-portion of the Homo sapiens hook homolog 3 (HOOK3) gene. The novel fusion was identified in a case of PTC that revealed a gene expression signature characteristic of RET/PTC on DNA microarray analysis, but was negative for the most common types of RET rearrangement. A fusion product between exon 11 of HOOK3 and exon 12 of RET gene was identified by 5'RACE, and the presence of chimeric HOOK3-RET protein of 88 kDa was detected by western blot analysis with an anti-RET antibody. The protein is predicted to contain a portion of the coiled-coil domains of HOOK3 and the intact TK domain of RET. Expression of the HOOK3-RET cDNA in NIH3T3 cells resulted in the formation of transformed foci and in tumor formation after injection into nude mice, confirming the oncogenic nature of HOOK3-RET.