Given that most thyroid cancers exhibit decreased or absent radioiodide accumulation, the prevailing expectation for a long time was that NIS expression would be found to be decreased or absent in cancerous thyrocytes. The first investigations addressing this issue, carried out using RT-PCR and showing lower mRNA levels in cancerous than in normal thyrocytes, seemed to confirm these expectations (24-28). RT-PCR is an easy-to-perform and very effective technique to detect mRNA expression even in very small tissue samples. However, determinations of mRNA levels by either RT-PCR or
Northern blot analysis provide no information on RNA stability. In addition, mRNA levels of proteins like NIS, with long half-lives and complex posttranscriptional regulation, do not necessarily correlate with actual protein expression (29). Immunoblot analyses to directly assess protein expression would address this limitation; however, this requires significantly larger tissue samples, which are not often available from human specimens.
Immunoblot analyses may provide satisfactory quantitative and qualitative information on NIS protein expression and some posttranslational modifications, but not on subcellular distribution. The subcellular localization of NIS is particularly significant because, as pointed out earlier, NIS is functional only when it is properly targeted to the plasma membrane. Hence, immunohistochemical analysis ofNIS expression in thyroid cancer was carried out (20, 30, 31). In addition to revealing the subcellular distribution of NIS, immunohistochemistry offers the advantage that NIS protein expression in the carcinomatous tissue can be compared to the surrounding normal tissue in the same thyroid gland. Surprisingly, immunohistochemical studies of NIS protein expression in thyroid cancer have shown that as many as 70% of thyroid cancers actually exhibit NIS protein overexpression (Figure 2B), as compared to the surrounding normal tissue, although in these cancerous cells NIS is mainly located in intracellular membrane compartments rather than in the plasma membrane. NIS was absent only in about 30% of the cases (20, 31). Thus far, no NIS mutations resulting in impaired protein expression or altered plasma membrane trafficking have been identified in thyroid cancer (32). These findings have had a significant impact on research approaches aiming to improve the effectiveness of radioiodide therapy, since they emphasize the importance of stimulating NIS targeting to and/or retention at the plasma membrane rather than stimulating NIS expression at the transcriptional level.
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