Alternative splicing-related factor YT521: an independent prognostic factor in endometrial cancer.
BACKGROUND
YT521 is a splicing factor involved in alternative splicing regulation of several tumor biological important genes. Two messenger RNA (mRNA) isoforms due to YT521 exon6 alternative splicing exist, with so far unknown functional consequences. Further evidence exists for a direct influence of YT521 expression in tumorigenesis because its mRNA level is changed in tumors compared with physiological tissue. We investigated the potential impact of YT521 expression on tumor biological parameters in endometrial cancer (EC).


METHODS
Real-time reverse transcription-polymerase chain reaction specifically detecting YT521 exon6-retention and exon6-skipping mRNA isoforms and immunohistochemistry were performed in a cohort of 130 EC tissue samples.


RESULTS
Whereas YT521 exon6-retention mRNA was detectable in 86 (66.2%), the exon6-skipping isoform mRNA was expressed in only 8 (6.2%) of all EC samples. On the protein level, 104 (80%) of EC samples showed nuclear expression. The mRNA levels of exon6-skipping isoform were not correlated to any of the clinicopathological parameters of EC. In contrast, YT521 exon6-retention mRNA expression was positively correlated to metastasis (R = 0.196, P = 0.026) and inversely correlated to the protein expression levels (R = -0.205, P = 0.019). In univariate analyses, higher levels of YT521 exon6-retention mRNA were correlated to a poorer progression-free survival (P = 0.003), and this is confirmed by multivariate analyses (P = 0.019). The negative YT521 protein expression was correlated to poorer overall and disease-specific survival (P = 0.036 and P = 0.034), respectively, in univariate analyses. They are also confirmed by multivariate analyses (P = 0.021 and P = 0.010, respectively).


CONCLUSIONS
We characterized for the first time in a clinical setting a new but rare exon6-skipping mRNA splicing isoform of YT521. Furthermore, we identified YT521 as a potential new independent prognostic factor for patients with EC: the lack of YT521 protein in tumor cells was highly predictive for a poor overall and disease-specific survival and independent from the histological subtypes.
Zhang
Bo
B
Department of Obstetrics and Gynecology, Freiburg University Medical Center, Freiburg, Germany.
zur Hausen
Axel
A
Orlowska-Volk
Marzenna
M
Jäger
Markus
M
Bettendorf
Herta
H
Stamm
Stefan
S
Hirschfeld
Marc
M
Yiqin
Ouyang
O
Tong
Xiaowen
X
Gitsch
Gerald
G
Stickeler
Elmar
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D014408:Biomarkers, Tumor / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007044:Hysterectomy; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor; D009419:Nerve Tissue Proteins; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C490769:YTHDC1 protein, human