WT1‐interacting protein inhibits cell proliferation and tumorigenicity in non‐small‐cell lung cancer via the AKT/FOXO1 axis

Abstract

Lung cancer is the most common cancer and the leading cause of cancer‐related death worldwide; hence, it is imperative that the mechanisms underlying the malignant properties of lung cancer be uncovered in order to efficiently treat this disease. Increasing evidence has shown that WT1‐interacting protein (WTIP) plays important roles both physiologically and pathologically in humans; however, the role of WTIP in cancer is unknown. Here, we investigated the role and mechanism of WTIP in cell proliferation and tumorigenesis of non‐small‐cell lung cancer (NSCLC). We report that WTIP is a tumor suppressor in human NSCLC. We found that WTIP expression was significantly reduced in both NSCLC cell lines and clinical specimens compared to that in normal controls; this reduction was largely attributed to promoter hypermethylation. Downregulation of WTIP significantly correlates with poor prognosis and predicts a shorter overall survival and progression‐free survival among NSCLC patients. Moreover, ectopic overexpression of WTIP dramatically inhibits cell proliferation and tumorigenesis in vitro and in vivo ; conversely, depletion of WTIP expression shows the opposite effects. Mechanistically, WTIP impairs AKT phosphorylation and activation, leading to enhanced expression and transcriptional activity of FOXO1, which further increases p21Cip1 and p27Kip1, and decreases cyclin D1, which consequently results in cell cycle arrest. Collectively, the results of the current study indicate that WTIP is an important proliferation‐related gene and that WTIP expression may represent a novel prognostic biomarker for NSCLC.

Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins

“…The presence of Zyxin in the nucleus and in the cytosol indicates its intriguing role in transcription or gene regulation (28,126). WTIP has a crucial role in cell proliferation and the downregulation of WTIP is associated with poor prognosis and survival of non-small-cell lung cancer patients (127). Interestingly, LIMD1, Ajuba, and WTIP discovered as a novel mammalian processing body (P-body) components and implicated in novel mechanisms of miRNA-mediated gene silencing (47).…”

“…Out of this TAGLN and CNN1 are reported as a putative marker for bladder cancer, whereas SMTN is reported to interact with Breast Cancer Metastasis Suppressor 1 (BRMS1), a protein known to suppress metastasis in multiple carcinomas (133,134). Many zyxin family proteins such as Zyxin, WTIP, and LPP, are directly implicated in the cancer prognosis and acts as a biomarker for certain tumorigenic conditions (40,127,133).…”

“…In addition to zyxin, other family members have also been linked to the cancer predisposition (see Table 1 for a full list of Zyxin family members). For example, WTIP has a crucial role in cell proliferation and downregulation of WTIP is associated with poor prognosis and survival of non-small-cell lung cancer patients [11]. Interestingly, LIMD1, Ajuba, and WTIP were discovered as novel mammalian processing body (P-body) components and implicated in novel mechanisms of miRNA-mediated gene silencing [12].…”

Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins

“…In addition to zyxin, other family members have also been linked to cancer predisposition (see Table 1 for a full list of Zyxin family members). For example, WTIP has a crucial role in cell proliferation and downregulation of WTIP is associated with poor prognosis and survival of non-small-cell lung cancer patients [ 11 ]. Interestingly, LIMD1,…”

Precision Nutrition and Cancer Relapse Prevention: A Systematic Literature Review

“…Other example of the last advances in this field is the detection of the scaffold WT1-interacting protein (WTIP) as a novel tumor suppressor down-modulated in NSCLC. Lower levels of these proteins significantly correlate with poor prognosis as a result of higher rates of cell proliferation and tumorigenesis [3]. Additionally, increasing findings in immunotherapy open expectations for the improvement of the prognosis of lung cancer patients [4].…”