Date Published: April 11, 2019
Publisher: Public Library of Science
Author(s): Mai Matsumura, Koji Okudela, Yu Nakashima, Hideaki Mitsui, Kaori Denda-Nagai, Takehisa Suzuki, Hiromasa Arai, Shigeaki Umeda, Yoko Tateishi, Chihiro Koike, Toshiaki Kataoka, Tatsuro Irimura, Kenichi Ohashi, Aamir Ahmad.
We investigated the significance of MUC21 in EGFR-mutated lung adenocarcinoma (LADC). Two-hundred forty-one surgically resected LADCs (116 EGFR-mutated and 125 wild-type tumors) were examined for immunohistochemical expression of MUC21 protein. A polyclonal antibody and two monoclonal antibodies (heM21C and heM21D) that bind differentially glycosylated MUC21 epitopes were used, and MUC21 proteins detected by these antibodies were named MUC21P, MUC21C, and MUC21D, respectively. MUC21 mRNA levels were semi-quantified and classified into “high” and “low”. Among the immunohistochemical expression detected by three different antibodies, high expressors tended to be related to EGFR mutations. The three varieties of the immunohistochemical expressions were related to different histological elements in the EGFR-mutated LADCs. Either MUC21P or MUC21C high expressors had a higher proportion of lepidic elements with low papillary structure and micropapillary elements. MUC21D high expressors had a significantly higher proportion of micropapillary elements (Mann-Whitney test P ≤0.0001). Furthermore, MUC21D high expressors showed high incidence of lymphatic canal invasion and lymph node metastasis (Pearson x2 test, P = 0.0021, P = 0.0125), and a significantly higher recurrence rate (5-year recurrence-free survival 50.7% vs. 73.8%, log-rank test P = 0.0495). MUC21 proteins with a specific glycosylation status may be involved in the progression of EGFR-mutated LADCs, particularly at the stage where tumors are transforming from pure lepidic to micropapillary through low papillary lepidic lesions.
EGFR-mutated lung adenocarcinoma (LADC) develops through a distinct histogenesis in which micropapillary (mPAP) elements promote tumor progression . However, the molecular basis of mPAP elements is not fully understood.
The most interesting finding was that the three varieties of MUC21 immunohistochemical expressions were related to different histological elements in EGFR-mutated LADCs. MUC21P and MUC21C were related to both LEPL and mPAP elements, and MUC21D was exclusively related to mPAP elements. The mPAP element is generated from a lepidic element through an intermediate LEPL element . Thus, MUC21 protein with a specific glycosylation status may be involved in the progression of EGFR-mutated LADCs, particularly at the stage where tumors are transforming from lepidic to mPAP through LEPL lesions. In particular, MUC21D may be an important factor to confer aggressiveness to mPAP because MUC21D high expressors had frequent lymphatic canal invasion and a high recurrence rate.