Targeting NUFIP1 Suppresses Growth and Induces Senescence of Colorectal Cancer Cells.

Aling Shen,Jiapeng Li,Qiurong Xie,Xiaoping Chen,Ying Cheng,Lihui Wei,Xiuli Zhang,Fenglin Chen,Li Li,Thomas J Sferra,Zhiqing Shen,Jun Peng,Liya Liu,Youqin Chen,Nanhui Xu,Mingkai Zhuang,Meizhu Wu,Jianfeng Chu

doi:10.3389/fonc.2021.681425

Abstract

NUFIP1 is an RNA-binding protein that interacts with fragile X mental retardation protein (FMRP) in the messenger ribonucleoprotein particle (mRNP). We previously showed that NUFIP1 was upregulated in colorectal cancer (CRC), but how the protein may contribute to the disease and patient prognosis is unknown. Here we combine database analysis, microarray, quantitative PCR, and immunohistochemistry of patients’ samples to confirm our previous findings on NUFIP1 overexpression in CRC, and to reveal that increased expression of NUFIP1 in CRC tissues correlated with worse overall, recurrence-free, event-free and disease-free survival in patients, as well as with more advanced CRC clinicopathological stage. Loss of function analysis demonstrated that NUFIP1 knockdown suppressed cell growth in vitro and in vivo, inhibited cell viability and survival, and induced cell cycle arrest and apoptosis in vitro, as well as up-regulated Bax and down-regulated Bcl-2 protein expression. In addition, as a natural anticancer triterpene from various fruits and vegetables, ursolic acid (UA) treatment suppressed cell proliferation, down-regulated NUFIP1 protein expression, and further enhanced the effects of NUFIP1 knockdown in CRC cells in vitro. NUFIP1 knockdown up-regulated the expression of 136 proteins, down-regulated the expression of 41 proteins, and enriched multiple signaling pathways including the senescence-associated heterochromatin foci (SAHF) pathway. Furthermore, NUFIP1 knockdown enhanced the expression of senescence-associated-β-galactosidase (SA-β-gal), the SAHF markers HP1γ and trimethylation (H3k9me3), and the senescence-related protein HMGA2, as well as both p53 and its downstream p21 protein expression. Our findings suggest that NUFIP1 is overexpressed in CRC and correlates with disease progression and poor patient survival. NUFIP1 may exert oncogenic effects partly by altering senescence. UA may show potential to treat CRC by down-regulating NUFIP1.

Highlights

Colorectal cancer (CRC) is the third most commonly diagnosed cancer type and the fourth leading cause of cancer mortality worldwide [1]
Using the R2 application and GEPIA dataset, we found that higher expression of NUFIP1 correlated with shorter recurrence-free survival (RFS), event-free survival (EFS; Figure 2E; P < 0.05), and disease-free survival (DFS; Figure 2F; P < 0.05)
We further explored the effects of NUFIP1 knockdown on cell proliferation and apoptosis in colorectal cancer (CRC) cells

Summary

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer type and the fourth leading cause of cancer mortality worldwide [1]. The incidence and mortality of CRC are increasing in China [2], and2.2 million new cases of CRC and 1.1 million deaths are predicted by 2030 in the world [3]. Many breakthroughs in the diagnosis and treatment of CRC have been made over the past few decades, CRC-related mortality remains high [4]. The progression of CRC is a multistep process involving the deregulation of several oncogenes and tumor suppressor genes, which might be used as diagnostic and therapeutic targets [5]. The precise mechanisms are poorly understood and novel diagnostic biomarkers need to be discovered [6]. Molecular mechanisms involved in the occurrence and development of CRC should be studied in depth to improve its early diagnosis and help predict relevant treatment targets

Methods

Results

Conclusion