NFIB overexpression cooperates with <i>Rb/p53</i> deletion to promote small cell lung cancer

Wu, Nan; Jia, Deshui; Ibrahim, Ali H.; Bachurski, Cindy J.; Gronostajski, Richard M.; MacPherson, David

doi:10.18632/oncotarget.11583

Cited by 64 publications

(65 citation statements)

References 28 publications

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“…Previous studies reported that NFIB played a controversial role in different cancers. Wu et al show that in Rb/p53 deletion mice, NFIB overexpression can accelerate small cell lung cancer formation. NFIB promotes cell proliferation in estrogen receptor‐negative breast cancers by upregulating CDK6 and downregulating p21 .…”

Section: Discussionmentioning

confidence: 99%

Nuclear factor I/B promotes colorectal cancer cell proliferation, epithelial‐mesenchymal transition and 5‐fluorouracil resistance

et al. 2018

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Nuclear factor I/B (NFIB) is a widely studied transcription factor that participates in tumor progression; nevertheless, studies on NFIB in colorectal cancer (CRC) are limited. In our study, Western blot and RT‐PCR analyses showed that NFIB was overexpressed in CRC tissues and cell lines, which was consistent with our bioinformatic analysis results. Furthermore, NFIB expression was closely related to the TNM stage of CRC. NFIB promoted cell proliferation and migration and inhibited cell apoptosis in vitro. Meanwhile, we discovered that NFIB accelerated xenograft tumor growth in vivo. In addition, NFIB weakened the sensitivity of CRC cells to 5‐fluorouracil (5‐FU). NFIB induced epithelial‐mesenchymal transition (EMT) by upregulating snail expression, which was accompanied by decreased E‐cadherin and Zo‐1 expression and increasedd Vimentin expression. Because the Akt pathway plays an important role in CRC progression, we examined whether there was a correlation between NFIB and the Akt pathway in cell proliferation and migration. Our results showed that NFIB promoted cell proliferation and increased 5‐FU resistance by activating the Akt pathway. In summary, our findings suggested that NFIB induced EMT of CRC cells via upregulating snail expression and promoted cell proliferation and 5‐FU resistance by activating the Akt pathway.

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Section: Discussionmentioning

confidence: 99%

Nuclear factor I/B promotes colorectal cancer cell proliferation, epithelial‐mesenchymal transition and 5‐fluorouracil resistance

et al. 2018

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“…Recent studies have shown that NFIB functions as a driver of metastasis and tumour progression in small cell lung cancer (SCLC) . In particular, NFIB overexpression in a pRB/p53‐inactivated mouse model accelerates small cell lung cancer progression, whereas reduced NFIB expression in this model suppresses cell proliferation and induces apoptosis, suggesting that NFIB cooperates with pRB/p53 inactivation to promote SCLC progression .…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have shown that NFIB functions as a driver of metastasis and tumour progression in small cell lung cancer (SCLC) [13][14][15]. In particular, NFIB overexpression in Role of NFIB in breast cancer cell survival 187 with pRB/p53 inactivation to promote SCLC progression [16].…”

Section: Introductionmentioning

confidence: 99%

NFIB promotes cell survival by directly suppressing p21 transcription in TP53‐mutated triple‐negative breast cancer

Liu

Jain

et al. 2018

The Journal of Pathology

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Triple‐negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited treatment options and poor prognosis. There is an urgent need to identify and understand the key factors and signalling pathways driving TNBC tumour progression, relapse, and treatment resistance. In this study, we report that gene copy numbers and expression levels of nuclear factor IB (NFIB), a recently identified oncogene in small cell lung cancer, are preferentially increased in TNBC compared to other breast cancer subtypes. Furthermore, increased levels of NFIB are significantly associated with high tumour grade, poor prognosis, and reduced chemotherapy response. Concurrent TP53 mutations and NFIB overexpression (z‐scores > 0) were observed in 77.9% of TNBCs, in contrast to 28.5% in non‐TNBCs. Depletion of NFIB in TP53‐mutated TNBC cell lines promotes cell death, cell cycle arrest, and enhances sensitivity to docetaxel, a first‐line chemotherapeutic drug in breast cancer treatment. Importantly, these alterations in growth properties were accompanied by induction of CDKN1A, the gene encoding p21, a downstream effector of p53. We show that NFIB directly interacts with the CDKN1A promoter in TNBC cells. Furthermore, knockdown of combined p21 and NFIB reverses the docetaxel‐induced cell growth inhibition observed upon NFIB knockdown, indicating that NFIB's effect on chemotherapeutic drug response is mediated through p21. Our results indicate that NFIB is an important TNBC factor that drives tumour cell growth and drug resistance, leading to poor clinical outcomes. Thus, targeting NFIB in TP53‐mutated TNBC may reverse oncogenic properties associated with mutant p53 by restoring p21 activity. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…However, GEMMs remain a key system in which to study the mechanisms of metastatic progression. Recently, three studies have highlighted a major role for the Nfib transcription factor in the metastatic progression of SCLC (14,15,21) ( Figure 2). The Nfib gene is frequently amplified in mouse tumors as they become metastatic (21,67); in human tumors NFIB is more rarely amplified (12,59,60) but high expression is found in over 50% of metastases.…”

Section: Metastatic Sclcmentioning

confidence: 99%

Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models

Shue¹,

Lim²,

Sage³

2018

Transl. Lung Cancer Res.

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Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer characterized by its fast growth and aggressive nature. SCLC development is strongly associated with heavy cigarette smoking. In a majority of cases, SCLC tumors have already metastasized to distant sites at the time of first diagnosis. Except in rare cases when tumors are diagnosed early, treatment options are limited and usually consist of several rounds of chemotherapy with cisplatin/ carboplatin and etoposide. While this chemotherapy regimen often results in significant response and tumor shrinkage, relapse is usually quite rapid. A number of excellent reviews have recently discussed the key clinical features of SCLC and the current lack of efficient treatment despite a large number of clinical trials in the past three decades (1-4). New therapeutic approaches, including immunotherapies, are promising but at the time this review is written, there are still no approved targeted therapies for SCLC [reviewed in (5-8)].Here we discuss emerging data in the field on the role of tumor heterogeneity in the growth of SCLC and the response of these tumors to therapy, and how mouse models have been used to identify such tumor heterogeneity and investigate its role. We use the term "intertumoral" heterogeneity to describe how SCLC tumors in patients or mice evolve differently at the genetic and epigenetic level during tumor progression and metastasis. We use the term "intratumoral" heterogeneity to describe the different subpopulations of cells within tumors at any given time; in Abstract: Small cell lung carcinoma (SCLC) is a fast-growing, highly metastatic form of lung cancer. A major difference between SCLC and other forms of lung cancer is that SCLC tumors often respond well to chemotherapy initially; unfortunately, resistant tumors rapidly recur. In addition, despite a large number of clinical trials with a variety of therapeutic agents, little progress has been achieved in the past three decades in improving the survival of SCLC patients. These clinical observations indicate that SCLC tumors have a high degree of plasticity and rapid adaptability to changes in growth conditions. Here we consider recent evidence pointing to several levels of heterogeneity in SCLC that may explain the ability of these tumors to adjust to different microenvironment and therapeutics. In particular, we review new data pointing to the existence of several subpopulations of tumor cells that interact with each other to promote tumor growth.We also discuss how SCLC tumors that look similar at the histopathological level may actually represent distinct subtypes of tumors and how these differences impact the response to specific therapeutic agents.A better understanding of genetic and cellular heterogeneity will guide the development of personalized approaches to help SCLC patients.

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NFIB overexpression cooperates with Rb/p53 deletion to promote small cell lung cancer

Cited by 64 publications

References 28 publications

Nuclear factor I/B promotes colorectal cancer cell proliferation, epithelial‐mesenchymal transition and 5‐fluorouracil resistance

Nuclear factor I/B promotes colorectal cancer cell proliferation, epithelial‐mesenchymal transition and 5‐fluorouracil resistance

NFIB promotes cell survival by directly suppressing p21 transcription in TP53‐mutated triple‐negative breast cancer

Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models

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