High prevalence of RET, RAS, and ERK expression in Hashimoto's thyroiditis and in papillary thyroid carcinoma in the Korean population.
BACKGROUND
The RET/PTC-RAS-BRAF cascade is associated with papillary thyroid carcinoma (PTC).


OBJECTIVE
The relationship between PTC and Hashimoto's thyroiditis (HT) is still elusive. To determine whether thyrocytes showing oxyphil cell metaplasia in HT also express RET, RAS, and ERK proteins, which are associated with PTC.


METHODS
We investigated the expression of RET, RAS, and ERK proteins in oxyphil cells in the vicinity of large lymphoid HT infiltrates and in malignant PTC cells. BRAF and N-RAS missense mutations were also examined in oxyphil cells of the HT. We used 47 PTC samples with no HT diagnosis, 28 PTC with HT, 39 HT with no PTC, and 36 HT with PTC. We also studied 75 normal portions of thyroid tissue from PTC specimens. Immunohistochemical analysis and polymerase chain reaction were used to determine activation of the RET/PTC-RAS-BRAF cascade in HT and PTC.


RESULTS
In PTC cells, HT oxyphil cells, and normal thyrocytes, the frequency of high RET expression was 23/70 (32.9%), 36/57 (63.2%), and 1/57 (1.8%) (p = 0.000); that of high nuclear localized RAS expression (nuclearRAS) was 65/71 (91.5%), 52/58 (89.7%), and 5/58 (8.6%) (p = 0.000); and that of high ERK expression was 38/70 (54.3%), 34/61 (55.7%), and 0/61 (0.0%) (p = 0.000), respectively. Of 66 HT cases studied for BRAF mutation and 57 HT cases studied for N-RAS mutation, no BRAF exon 15 or N-RAS exon 2 mutations were found in the amplified DNA extracted from oxyphil cells excised by laser capture microdissection.


CONCLUSIONS
The expression of RET, nuclearRAS, and ERK proteins is greatly enhanced in PTC cells and HT oxyphil cells. Thus, the RET/PTC-RAS-BRAF cascade may be involved in the development of PTC and oxyphil cell metaplasia in HT. Our results show the possibility of a molecular link between oxyphil cell metaplasia in HT and the progression of PTC.
Kang
Dae-Young
DY
Department of Pathology and Cancer Research Institute, Chungnam National University College of Medicine, Daejeon, Korea.
Kim
Kyung-Hee
KH
Kim
Jin-Man
JM
Kim
Seok-Hyung
SH
Kim
Ji-Young
JY
Baik
Haing-Woon
HW
Kim
Yong-Sung
YS
D044466:Asian People / Q000235:genetics; D002291:Carcinoma, Papillary / Q000150:complications / Q000235:genetics* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics*; D015870:Gene Expression; D050031:Hashimoto Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007723:Korea; D024862:Oxyphil Cells / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D018631:ras Proteins / Q000235:genetics*
D051096:Proto-Oncogene Proteins c-ret; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins