Silencing RIF1 decreases cell growth, migration and increases cisplatin sensitivity of human cervical cancer cells

Mei, Ying; Chen, Peng; Liu, Yongbin; Wang, Jing; Zhou, Hong‐Hao

doi:10.18632/oncotarget.22315

Cited by 21 publications

(17 citation statements)

References 24 publications

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“…Furthermore, knockdown of RIF1 inhibited DSB repair capacity and cell survival upon cisplatin treatment. These results were consistent with our previous findings in cervical cancer cells 21 .…”

Section: Discussionsupporting

confidence: 94%

Effect of RIF1 on response of non-small-cell lung cancer patients to platinum-based chemotherapy by regulating MYC signaling pathway

Mei

Liu

et al. 2018

Int. J. Biol. Sci.

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Platinum-based chemotherapy is used as first-line therapy for advanced non-small-cell lung cancer (NSCLC). However, there is no effective indicator to predict whether the patient would be chemo-resistant or sensitive to the therapy. In addition, it is urgent to elucidate the mechanisms of cisplatin resistance. RIF1 plays important roles in DNA replication regulation and DNA repair pathway. However, the role of RIF1 in NSCLC progression and chemotherapy response is still unknown. In this study, we found that RIF1 expression was correlated with the response of NSCLC patients to platinum-based chemotherapy (n=89, P=0.002). Among patients who have been treated with platinum chemo-therapy, those with high levels of RIF1 expression had significantly shorter survival than those with low RIF1 expression (P<0.05). RIF1 knockdown increased sensitivity to cisplatin in NSCLC patients both in vitro and in vivo. Moreover, RIF1 knockdown induced G0/G1 phase arrest and increased cisplatin-induced apoptosis and DNA damage. Further investigation showed that RIF1 regulated the expression of MYC and MYC downstream targets, including the cell cycle and double-stranded break (DSB) repair genes which might mediate the effect of RIF1 on cellular response to cisplatin. Overexpression of MYC could reverse the inhibition of MYC targets by RIF1 knockdown. Taken together, these data revealed that RIF1 played an important role in regulating MYC and MYC-activated genes, which in turn contributes to cellular response to cisplatin and NSCLC patients' response to platinum-based chemotherapy. RIF1 might serve as a novel biomarker for predicting platinum-based chemo-sensitivity and the prognosis of NSCLC patients, so as to guide the chemotherapy regimen adjustment for individual patient with NSCLC and improve their clinical outcomes.

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Section: Discussionsupporting

confidence: 94%

Effect of RIF1 on response of non-small-cell lung cancer patients to platinum-based chemotherapy by regulating MYC signaling pathway

Mei

Liu

et al. 2018

Int. J. Biol. Sci.

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“…Moreover, our previous study [52] found that silencing RIF1 increased cisplatin-induced apoptosis in human cervical cancer cells. Hence, it is possible that RIF1 knockdown potentiated ovarian cancer cells to platinum-based cancer treatment by disrupting the NER activity followed by increasing the apoptosis event.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of RIF1 Enhances Sensitivity to Platinum-Based Chemotherapy in Epithelial Ovarian Cancer (EOC) by Regulating Nucleotide Excision Repair (NER) Pathway

Liu

Mei

Tian

et al. 2018

Cell Physiol Biochem

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Background/Aims: Rap1 interacting factor 1 (RIF1) was deemed to be involved in replication timing regulation and DNA damage response. However, little is known about the role of RIF1 in malignancies. Thus, this study aimed to investigate whether the expression of RIF1 is relevant to the response of epithelial ovarian cancer (EOC) patients to cisplatin chemotherapy and its underlying mechanism. Methods: Immunohistochemistry was used for detecting the expression of RIF1 in 72 human ovarian cancer tissues followed by association analysis of RIF1 expression with patients’ responses to platinum-based chemotherapy. The survival analysis of ovarian patients based on platinum chemotherapy was analyzed using online databases. RNA interference of RIF1 was carried out in OVCAR3 and A2780 cell lines, to determine the effect of lacking RIF1 expression on cellular responses to cisplatin by using MTS assay. The nucleotide excision repair (NER) capacity of these cells was assessed by using host-cell reactivation and UV sensitivity assay. Western Blot analysis was carried out to determine the effect of RIF1 on the proteins of NER and apoptosis signaling pathway by using RIF1 knockdown cells. BALB/c nude mice model was used for detection of response to cisplatin in vivo. Results: RIF1 expression was significantly associated with the response of ovarian patients to platinum-based chemotherapy (P< 0.01). In cohorts from online databases, high expression of RIF1 was associated with higher mortality of EOC patients based on platinum chemotherapy (P < 0.01). RIF1 knockdown increased sensitivity to cisplatin in EOC in vitro and in vivo. Deletion of RIF1 impaired the NER activity by inhibiting the NER proteins in ovarian cancer cells. Besides, knockdown of RIF1 enhanced cisplatin-induced apoptosis. Conclusions: RIF1 plays an important role in regulating the expression of NER proteins, which in turn contributes to cellular response to cisplatin and EOC patients’ response to platinum-based chemotherapy. RIF1 knockdown also promotes cisplatin-induced apoptosis. RIF1 may serve as a novel biomarker for predicting platinum-based chemosensitivity and the prognosis of EOC patients.

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“…Besides, RIF1 is also involved in embryonic stem cells (ESCs) self-renewal and is highly expressed in mouse ESCs 20 – 22 . In addition, RIF1 has been reported overexpressed in breast cancer tissues and we previously found that RIF1 knockdown could decrease cell growth and increase cisplatin sensitivity of cervical and ovarian cancer cells 23 – 25 . Despite the roles listed above, the specific role of RIF1 in NSCLC remains little known.…”

Section: Introductionmentioning

confidence: 87%

RIF1 promotes tumor growth and cancer stem cell-like traits in NSCLC by protein phosphatase 1-mediated activation of Wnt/β-catenin signaling

et al. 2018

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Wnt/β-catenin signaling is essential for proliferation and maintenance of cancer stem cell-like traits of various cancer cells. In non-small-cell lung carcinoma (NSCLC), the mechanisms underlying the hyperactivation of Wnt signaling remain unclear, as mutations in APC and β-catenin genes are rare in NSCLC. RIF1 has been shown upregulated in breast and cervical cancer, this study intends to find out the potential effects of the expression and biological functions of RIF1 in NSCLC. Here we revealed that RIF1 was highly expressed in NCSLC at both mRNA and protein levels. RIF1 expression was significantly associated with clinical stage (P < 0.05) and prognosis (P < 0.001) of NSCLC patients. RIF1 knockdown inhibited NSCLC cell growth in vitro and in vivo, whereas overexpression of RIF1 in NSCLC cell lines promoted cell growth, cell cycle progression and cancer stem cell (CSC)-like properties via promoting PP1–AXIN interaction and thereby activating Wnt/β-catenin signaling. Inhibition of PP1 in RIF1-overexpressed cells counteracted the effects of RIF1 on cell growth and CSC-like phenotype, as well as the Wnt/β-catenin signaling. RIF1 expression was positively correlated with β-catenin at the protein level in 32 NSCLC tissues. RIF1 expression closely related to MYC (r = 0.28, P < 0.001) and CCND1 (r = 0.14, P < 0.01) expression at the mRNA level in cohorts of The Cancer Genome Atlas (TCGA). These results indicated that RIF1 had an oncogenic role as a novel positive regulator of Wnt/β-catenin signaling by directing PP1 to dephosphorylate AXIN; this novel mechanism may present a new therapeutic target for NSCLC.

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Silencing RIF1 decreases cell growth, migration and increases cisplatin sensitivity of human cervical cancer cells

Cited by 21 publications

References 24 publications

Effect of RIF1 on response of non-small-cell lung cancer patients to platinum-based chemotherapy by regulating MYC signaling pathway

Effect of RIF1 on response of non-small-cell lung cancer patients to platinum-based chemotherapy by regulating MYC signaling pathway

Downregulation of RIF1 Enhances Sensitivity to Platinum-Based Chemotherapy in Epithelial Ovarian Cancer (EOC) by Regulating Nucleotide Excision Repair (NER) Pathway

RIF1 promotes tumor growth and cancer stem cell-like traits in NSCLC by protein phosphatase 1-mediated activation of Wnt/β-catenin signaling

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