<i><scp>TIMELESS</scp></i> is overexpressed in lung cancer and its expression correlates with poor patient survival

Yoshida, Kenya; Sato, Mitsuo; Hase, Takashi; Elshazley, Momen; Yamashita, Riu; Usami, Noriyasu; Taniguchi, Tetsuo; Yokoi, Kohei; Nakamura, Shigeo; Kondo, Masashi; Girard, Luc; Minna, John D.; Hasegawa, Yoshinori

doi:10.1111/cas.12068

Cited by 58 publications

(51 citation statements)

References 18 publications

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“…Other studies have shown that TIPIN and TIM are under‐expressed in kidney (Mazzoccoli et al., 2012) and pancreatic (Relles et al., 2013) cancers. By contrast, TIM is overexpressed in bladder (Schepeler et al., 2013) and lung (Yoshida et al., 2013) cancers. We found that the levels of TIPIN mRNA and the proliferation marker Ki67 were strongly positively correlated (p < 2.2 × 10 −16 in the entire population; p = 0.008 in TNBC).…”

Section: Discussionmentioning

confidence: 99%

TIPIN depletion leads to apoptosis in breast cancer cells

et al. 2015

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Triple-negative breast cancer (TNBC) is the breast cancer subgroup with the most aggressive clinical behavior. Alternatives to conventional chemotherapy are required to improve the survival of TNBC patients. Gene-expression analyses for different breast cancer subtypes revealed significant overexpression of the Timeless-interacting protein (TIPIN), which is involved in the stability of DNA replication forks, in the highly proliferative associated TNBC samples. Immunohistochemistry analysis showed higher expression of TIPIN in the most proliferative and aggressive breast cancer subtypes including TNBC, and no TIPIN expression in healthy breast tissues. The depletion of TIPIN by RNA interference impairs the proliferation of both human breast cancer and non-tumorigenic cell lines. However, this effect may be specifically associated with apoptosis in breast cancer cells. TIPIN silencing results in higher levels of single-stranded DNA (ssDNA), indicative of replicative stress (RS), in TNBC compared to non-tumorigenic cells. Upon TIPIN depletion, the speed of DNA replication fork was significantly decreased in all BC cells. However, TIPIN-depleted TNBC cells are unable to fire additional replication origins in response to RS and therefore undergo apoptosis. TIPIN knockdown in TNBC cells decreases tumorigenicity in vitro and delays tumor growth in vivo. Our findings suggest that TIPIN is important for the maintenance of DNA replication and represents a potential treatment target for the worst prognosis associated breast cancers, such as TNBC.

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Section: Discussionmentioning

confidence: 99%

TIPIN depletion leads to apoptosis in breast cancer cells

et al. 2015

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“…Surprisingly, timeless gene expression, unlike other circadian clock genes, is observed to be higher in cancer cells and tissue compared to its expression in healthy tissue . Its elevated expression has in fact been proposed to be a poor prognostic marker in certain cancer types .…”

Section: Core Circadian Clock Genes Are Dysregulated In Cancer Cellsmentioning

confidence: 99%

The tumour suppressing role of the circadian clock

et al. 2019

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The circadian clock and the ~24 h rhythms it generates are essential in maintaining regular tissue functioning. At the molecular level, the circadian clock comprises a core set of rhythmically expressed genes and gene products that are able to drive rhythmic expression of other genes to generate overt circadian rhythms. It has recently come to light that perturbations of circadian rhythms contribute to the development of pathological states such as cancer, and altered expression and/or regulation of circadian clock genes has been identified in multiple tumour types. This review summarises the important role the circadian system plays in regulating cellular processes, including the cell cycle, apoptosis, DNA repair, the epithelial‐to‐mesenchymal transition, metabolism and immunity and how its dysregulation has widespread implications and could be a critical player in the development of cancer. Understanding its role in cancer development is important for the field chronotherapy, where the timing of chemotherapy administration is optimised based on differences in circadian clock functioning in normal and cancer cells. This has been found to influence the patient response, minimising the side effects commonly associated with chemotherapy. © 2019 IUBMB Life, 2019

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“…Precisely its expression is enhanced in lung cancer cell lines where its knockdown was related to the induction of apoptosis, suppression of proliferation, and clonogenic growth [34]. In surgically resected specimens from 88 consecutive patients, high TIM protein levels as gauged by immunohistochemistry (IHC) correlated with poor overall survival [34,35].…”

Section: Clock Genes and Circadian Regulationmentioning

confidence: 99%

Integration of Chronobiological Concepts for NSCLC Management

Focan¹,

Davin²,

Bourhaba³

et al. 2019

Chronobiology - The Science of Biological Time Structure

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The authors reviewed pertinent experimental and clinical data allowing to consider the interest of taking into account the temporal dimension ('circadian') for prevention and management of the majority of cancers, i.e., non-small cell lung carcinoma (NSCLC). The universal importance of circadian rhythms has been acknowledged in animal or human situations regarding carcinogenesis and cancer promotion; cell kinetics, apoptosis, molecular genetics, as well as DNA repair mechanisms, platinum resistance…; molecular targets (i.e., epidermal growth factor reception-EGFR); and all lymphoid and immunology machinery components. Also chronotolerance to all chemotherapeutic agents useful for treating human lung cancer has also been evidenced. A few randomized clinical chronotherapy trials were performed in human NSCLC. One limited trial has shown apparent chronoefficiency, while in another one, chronotolerance to 5-fluorouracil and a platinum derivative were confirmed. The limited improvement of outcome in human NSCLC, even through the use of targeted and biological therapies (such as tyrosine-kinase (TKI) or vascular-endothelialgrowth-factor (VEGFR) inhibitors; immunotherapy), allows to consider launching specific trials in human NSCLC aiming at either restoring a normal circadian structure of the host or taking into account circadian variations of specific targets. By now unfortunately, no targeted or immunotherapy trials have been launched considering temporal dimension.

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TIMELESS is overexpressed in lung cancer and its expression correlates with poor patient survival

Cited by 58 publications

References 18 publications

TIPIN depletion leads to apoptosis in breast cancer cells

TIPIN depletion leads to apoptosis in breast cancer cells

The tumour suppressing role of the circadian clock

Integration of Chronobiological Concepts for NSCLC Management

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