Oncotarget

Research Papers:

Disturbed alternative splicing of FIR (PUF60) directed cyclin E overexpression in esophageal cancers

Yukiko Ogura, Tyuji Hoshino, Nobuko Tanaka, Guzhanuer Ailiken, Sohei Kobayashi, Kouichi Kitamura, Bahityar Rahmutulla, Masayuki Kano, Kentarou Murakami, Yasunori Akutsu, Fumio Nomura, Sakae Itoga, Hisahiro Matsubara and Kazuyuki Matsushita _

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Oncotarget. 2018; 9:22929-22944. https://doi.org/10.18632/oncotarget.25149

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Abstract

Yukiko Ogura1, Tyuji Hoshino2, Nobuko Tanaka3, Guzhanuer Ailiken4, Sohei Kobayashi1,3, Kouichi Kitamura3,4, Bahityar Rahmutulla5, Masayuki Kano1, Kentarou Murakami1, Yasunori Akutsu1, Fumio Nomura3, Sakae Itoga3, Hisahiro Matsubara1 and Kazuyuki Matsushita3

1Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan

2Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan

3Department of Laboratory Medicine & Division of Clinical Genetics and Proteomics, Chiba University Hospital, Chiba, Japan

4Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan

5Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan

Correspondence to:

Kazuyuki Matsushita, email: [email protected]

Keywords: esophageal squamous cell carcinoma (ESCC); alternative splicing (AS); FBW7; FIR (PUF60); cyclin E

Received: May 25, 2017    Accepted: March 22, 2018    Published: May 01, 2018

ABSTRACT

Overexpression of alternative splicing of far upstream element binding protein 1 (FUBP1) interacting repressor (FIR; poly(U) binding splicing factor 60 [PUF60]) and cyclin E were detected in esophageal squamous cell carcinomas (ESCC). Accordingly, the expression of FBW7 was examined by which cyclin E is degraded as a substrate via the proteasome system. Expectedly, FBW7 expression was decreased significantly in ESCC. Conversely, c-myc gene transcriptional repressor FIR (alias PUF60; U2AF-related protein) and its alternative splicing variant form (FIRΔexon2) were overexpressed in ESCC. Further, anticancer drugs (cis-diaminedichloroplatinum/cisplatin [CDDP] or 5-fluorouracil [5-FU]) and knockdown of FIR by small interfering RNA (siRNA) increased cyclin E while knockdown of FIRΔexon2 by siRNA decreased cyclin E expression in ESCC cell lines (TE1, TE2, and T.Tn) or cervical SCC cells (HeLa cells). Especially, knockdown of SAP155 (SF3b1), a splicing factor required for proper alternative splicing of FIR pre-mRNA, decreased cyclin E. Therefore, disturbed alternative splicing of FIR generated FIR/FIRΔexon2 with cyclin E overexpression in esophageal cancers, indicating that SAP155 siRNA potentially rescued FBW7 function by reducing expression of FIR and/or FIRΔexon2. Remarkably, Three-dimensional structure analysis revealed the hypothetical inhibitory mechanism of FBW7 function by FIR/FIRΔexon2, a novel mechanism of cyclin E overexpression by FIR/FIRΔexon2-FBW7 interaction was discussed. Clinically, elevated FIR expression potentially is an indicator of the number of lymph metastases and anti-FIR/FIRΔexon2 antibodies in sera as cancer diagnosis, indicating chemical inhibitors of FIR/FIRΔexon2-FBW7 interaction could be potential candidate drugs for cancer therapy. In conclusion, elevated cyclin E expression was, in part, induced owing to potential FIR/FIRΔexon2–FBW7 interaction in ESCC.


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