Overexpression of tumor susceptibility gene TSG101 in human papillary thyroid carcinomas

Abstract

Functional inactivation of tumor susceptibility gene tsg101 leads to cellular transformation and tumorigenesis in mice. While human TSG101 is located in a region where frequent loss of heterozygosity can be detected in a variety of cancers, no genomic deletion in TSG101 gene has been reported, casting a doubt on the role of TSG101 as a classical tumor suppressor. Some studies have revealed that TSG101 is a frequent target of splicing defects, which correlate with cellular stress and p53 status. Furthermore, recent reports have identified TSG101 as a part of the MDM2/p53 regulatory circuitry, a well-recognized circuitry that upon deregulation results in tumorigenesis. Interestingly, overexpression of tsg101 from an adventitious promoter also leads to neoplastic transformation. On the basis of this information, we have analysed TSG101 gene expression in 20 human papillary thyroid carcinomas (PTCs) by immunohistochemistry and demonstrated that the overexpression of TSG101 protein is closely associated with human PTCs. Further sequence analysis reveals no mutation in cDNA region encoding steadiness box in these PTC specimens, indicating that the upregulation of TSG101 protein is not caused by the alteration of this region. In situ hybridization analysis confirms that overexpression of TSG101 also occurs at the transcriptional level. In addition, semi-quantitative RT -PCR and subsequent Southern hybridization verify that the amounts of TSG101 transcripts are indeed lower in three normal thyroid tissues than in PTC specimens. Here we report the upregulation of TSG101 expression in PTC cells, providing the first evidence of the association of TSG101 overexpression with human tumors and suggesting that upregulation of TSG101 steady-state level might play a role in mediating tumorigenesis of human PTC.

TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation

“…However, excessive production of TSG101 also can promote abnormal cell growth (10), consistent with evidence for a cellular imperative to maintain TSG101 levels within a narrow range (19). Aberrant splicing of, partial deletions in, or overproduction of TSG101 protein have been reported to occur in human cancers (45)(46)(47)(48). Consistent with a crucial role of the intracellular level of TSG101 in determining its actions is evidence that cells that totally lack TSG101 cannot be propagated (8,9), whereas a lesser deficiency of TSG101 allows cell survival while still yielding prominent effects on endosomal trafficking and other biological processes (10,17,23,24).…”

Reduction of TSG101 protein has a negative impact on tumor cell growth

“…16 However, a recent immunohistochemical study of TSG101 in human papillary thyroid carcinomas (PTCS) has shown that TSG101 expression levels were higher in PTCS than they were in normal cells. 17 We too have found TSG101 to be overexpressed in breast cancer cells, while the normal breast epithelial cells showed negative staining, though we did observe also that levels of this protein were decreased at the peripheral margin of the tumor. 1 Thus, whether TSG101 is consistently under-or overexpressed in a range of neoplastic tissues is not yet determined.…”

Tsg101 is upregulated in a subset of invasive human breast cancers and its targeted overexpression in transgenic mice reveals weak oncogenic properties for mammary cancer initiation

“…Tsg101 is upregulated in a subset of invasive human breast cancers There are only very few published studies that utilized methods other than reverse transcriptase-polymerase chain reaction (RT-PCR) to determine the expression of Tsg101 in primary human carcinomas (Lo et al, 2000;Liu et al, 2002;Zhu et al, 2003). All these reports demonstrated that the Tsg101 protein was expressed, albeit at heterogeneous levels, in normal and neoplastic tissues.…”

“…Although the expression of Tsg101 appeared to be upregulated in selected human cancers (Lo et al, 2000;Liu et al, 2002;Zhu et al, 2003;and this report), the paradigm of Tsg101 as an oncogene has never been experimentally addressed using an appropriate in vivo model system. To test whether excess levels of Tsg101 are sufficient to trigger neoplastic transformation, we generated a transgenic mouse model that overexpresses wild-type Tsg101 in the developing mammary gland.…”