title: TIMELESS is overexpressed in lung cancer and its expression correlates with poor patient survival.
abstract: TIMELESS (TIM) is a mammalian homolog of a Drosophila circadian rhythm gene, but its circadian properties in mammals have yet to be determined. TIM appears to be essential for replication protection and genomic stability. Recently, the involvement of TIM in human malignancies has been reported; therefore, we investigated the role of TIM in lung cancer. Microarray expression analysis of lung cancer cell lines showed that TIM expression was elevated 3.7-fold (P < 0.001) in non-small cell lung cancer cell lines (n = 116) compared to normal lung controls (n = 59). In addition, small cell lung cancer cell lines (n = 29) expressed TIM at levels 2.2-fold (P < 0.001) higher than non-small cell lung cancer. Western blot analysis of 22 lung cancer cell lines revealed that all of them expressed TIM protein and that 20 cell lines (91%) expressed TIM protein at higher levels than a normal control line. Remarkably, immunohistochemistry of 30 surgically resected lung cancer specimens showed that all lung cancer specimens but no matched normal lung tissues were positive for TIM expression. Moreover, immunohistochemistry of surgically resected specimens from 88 consecutive patients showed that high TIM protein levels correlated with poor overall survival (P = 0.013). Mutation analysis for TIM in 23 lung cancer cell lines revealed no mutation. TIM knockdown suppressed proliferation and clonogenic growth, and induced apoptosis in H157 and H460 cells. Taken together, our findings suggest that TIM could be useful as a diagnostic and prognostic marker for lung cancer and targeting it would be of high therapeutic value for this disease.
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kenya
authors.initials: K
authors.lastname: Yoshida
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Sato
authors.forename: Tetsunari
authors.initials: T
authors.lastname: Hase
authors.forename: Momen
authors.initials: M
authors.lastname: Elshazley
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamashita
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Usami
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Kohei
authors.initials: K
authors.lastname: Yokoi
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakamura
authors.forename: Masashi
authors.initials: M
authors.lastname: Kondo
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects; D011379:Prognosis; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; C509769:TIMELESS protein, human; D004317:Doxorubicin; D002945:Cisplatin