Reduced Expression of RanBPM Is Associated with Poorer Survival from Lung Cancer and Increased Proliferation and Invasion of Lung Cancer Cells In Vitro

Zhao, Zehang; Cheng, Shan; Zabkiewicz, Catherine; Chen, Jinfeng; Zhang, Lijiang; Lin, Ye; Jiang, Wen Guo

doi:10.21873/anticanres.11833

Cited by 5 publications

(11 citation statements)

References 30 publications

(36 reference statements)

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“…However, RANBP9 appears to be rarely mutated and mostly overexpressed rather than downregulated in all types of cancers (Table S3). A recent analysis of a cohort of stage I and II LC patients suggested a positive correlation of higher levels of RANBP9 mRNA with better LC prognosis [37] in apparent contrast with our current findings. However, this latter study was exclusively based on mRNA expression and highly biased for early stage cases.…”

Section: Discussioncontrasting

confidence: 99%

RANBP9 affects cancer cells response to genotoxic stress and its overexpression is associated with worse response to platinum in NSCLC patients

et al. 2018

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Although limited by severe side effects and development of resistance, platinum-based therapies still represent the most common first-line treatment for non-small cell lung cancer (NSCLC). However, a crucial need in the clinical management of NSCLC is represented by the identification of cases sensitive to DNA damage response (DDR)-targeting drugs, such as cisplatin or PARP inhibitors. Here, we provide a molecular rationale for the stratification of NSCLC patients potentially benefitting from platinum compounds based on the expression levels of RANBP9, a recently identified player of the cellular DDR. RANBP9 was found overexpressed by immunohistochemistry (IHC) in NSCLC compared to normal adjacent tissues (NATs) (n = 147). Moreover, a retrospective analysis of 132 platinum-treated patients from the multi-centric TAILOR trial showed that RANBP9 overexpression levels are associated with clinical response to platinum compounds [Progression Free Survival Hazard Ratio 1.73, 95% CI 1.15-2.59, p = 0.0084; Overall Survival HR 1.99, 95% CI 1.27-3.11, p = 0.003]. Accordingly, RANBP9 KO cells showed higher sensitivity to cisplatin in comparison with WT controls both in vitro and in vivo models. NSCLC RANBP9 KO cells were also more sensitive than control cells to the PARP inhibitor olaparib alone and in combination with cisplatin, due to defective ATM-dependent and hyper-activated PARP-dependent DDR. The current investigation paves the way to prospective studies to assess the clinical value of RANBP9 protein levels as prognostic and predictive biomarker of response to DDR-targeting drugs, leading to the development of new tools for the management of NSCLC patients.

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Section: Discussioncontrasting

confidence: 99%

RANBP9 affects cancer cells response to genotoxic stress and its overexpression is associated with worse response to platinum in NSCLC patients

et al. 2018

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“…The present study revealed that RANBP9 may be a potential anti-oncogene in CRC. These results were consistent with studies on osteosarcoma, lung and gastric cancer (10–13).…”

Section: Discussionsupporting

confidence: 93%

“…The present study demonstrated that RANBP9 exhibited an inhibitory role in CRC, yet it remains unclear why malignant cells overexpress RANBP9. Similar phenomena have been observed in osteosarcoma, lung and gastric cancer (10–13). Cancer cells are associated with different sets of oncogenes and tumor suppressor genes that are normally involved in stabilizing negative feedback loops.…”

Section: Discussionsupporting

confidence: 84%

“…Similar to the majority of RAN binding proteins, RANBP9 is functionally associated with the β-importin receptor family, which is responsible for transporting proteins into the nucleus (8). Additionally, RANBP9 has been associated with osteosarcoma, lung, gastric and breast cancer (10–14); however, its systematic effects in cancer remain to be investigated.…”

Section: Introductionmentioning

confidence: 99%

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RANBP9 suppresses tumor proliferation in colorectal cancer

Qin

Zhang

2019

Oncol Lett

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RAN binding protein 9 (RANBP9) is widely expressed in mammalian tissues, including osteosarcoma, lung, gastric and breast cancer tissues. However, currently, not much is known about the role of RANBP9 in colorectal cancer (CRC). In the present study, RANBP9 expression in CRC tissues and cell lines was measured by immunohistochemistry and western blotting, respectively. Subsequently, RANBP9 -short hairpin RNA (shRNA) and RANBP9 plasmids were constructed and transfected into HCT116 and HT29 cells. The effects of RANBP9 knockdown were assessed by Cell Counting kit-8 and colony formation assays, and its effects on tumorigenicity in a nude mouse animal model were investigated. The effect of RANBP9 -shRNA on cell cycle progression was analyzed by flow cytometry, while cell cycle-associated protein expression levels were examined by western blotting. Compared with in paired normal mucosa, RANBP9 was overexpressed in CRC tissues. Inhibition of RANBP9 in HCT116 and HT29 cells significantly promoted cell growth, colony formation and S phase transition, and increased tumorigenesis in vivo . Accordingly, RANBP9 overexpression inhibited cell growth and colony formation. Knockdown of RANBP9 was associated with upregulated cyclin A2 in the two cell lines. In conclusion, RANBP9 served an inhibitory role in CRC in vitro and in vivo . Therefore, RANBP9 may be considered a potential target for treatment of CRC.

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“…As RanBPM downregulation was previously reported to result in increased cellular proliferation [21,26], we evaluated whether the loss of RMND5A could also confer similar properties. Comparison of growth curves of wild-type (WT) and three different RMND5A CRISPR knockout HEK293 clonal derivatives showed that control cells slowed down after four days, whereas cells lacking RMND5A proliferated markedly faster starting at day 3 (Figure 1C).…”

Section: Resultsmentioning

confidence: 99%

Regulation of c-Raf Stability through the CTLH Complex

McTavish

Bérubé-Janzen

Wang

et al. 2019

IJMS

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c-Raf is a central component of the extracellular signal-regulated kinase (ERK) pathway which is implicated in the development of many cancer types. RanBPM (Ran-Binding Protein M) was previously shown to inhibit c-Raf expression, but how this is achieved remains unclear. RanBPM is part of a recently identified E3 ubiquitin ligase complex, the CTLH (C-terminal to LisH) complex. Here, we show that the CTLH complex regulates c-Raf expression through a control of its degradation. Several domains of RanBPM were found necessary to regulate c-Raf levels, but only the C-terminal CRA (CT11-RanBPM) domain showed direct interaction with c-Raf. c-Raf ubiquitination and degradation is promoted by the CTLH complex. Furthermore, A-Raf and B-Raf protein levels are also regulated by the CTLH complex, indicating a common regulation of Raf family members. Finally, depletion of CTLH subunits RMND5A (required for meiotic nuclear division 5A) and RanBPM resulted in enhanced proliferation and loss of RanBPM promoted tumour growth in a mouse model. This study uncovers a new mode of control of c-Raf expression through regulation of its degradation by the CTLH complex. These findings also uncover a novel target of the CTLH complex, and suggest that the CTLH complex has activities that suppress cell transformation and tumour formation.

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Reduced Expression of RanBPM Is Associated with Poorer Survival from Lung Cancer and Increased Proliferation and Invasion of Lung Cancer Cells In Vitro

Abstract: Increased expression of RanBPM associates with postponed disease progression and better prognosis. RanBPM plays an inhibitory role in regulating proliferation and invasion of lung cancer cells.

Cited by 5 publications

References 30 publications

RANBP9 affects cancer cells response to genotoxic stress and its overexpression is associated with worse response to platinum in NSCLC patients

RANBP9 affects cancer cells response to genotoxic stress and its overexpression is associated with worse response to platinum in NSCLC patients

RANBP9 suppresses tumor proliferation in colorectal cancer

Regulation of c-Raf Stability through the CTLH Complex

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