FOXO1: Another avenue for treating digestive malignancy?

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Review

FOXO1: Another avenue for treating digestive malignancy? Feiyu Shia,1, Tian Lib,1, Zhi Liuc,1, Kai Qud, Chengxin Shia, Yaguang Lia, Qian Qina, Liang Chenga, ⁎ Xin Jina, Tianyu Yua, Wencheng Die, Jianwen Quef, Hongping Xiag, Junjun Shea, a

Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, Xi’an 710061, Shaanxi, China Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi’an 710032, Shaanxi, China Department of Stomatology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi’an 710061, Shaanxi, China d Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi’an 710061, Shaanxi, China e Department of Cardiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China f Center for Human Development & Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, 10032, NY, USA g Laboratory of Cancer Genomics, National Cancer Centre, Singapore 169610, Singapore b c

A R T I C L E I N F O

A B S T R A C T

Keyword: Forkhead box O1 Digestive malignancy Hepatocellular carcinoma Akt microRNA

Digestive malignancies are the leading cause of mortality among all neoplasms, contributing to estimated 3 million deaths in 2012 worldwide. The mortality rate hassurpassed lung cancer and prostate cancer in recent years. The transcription factor Forkhead Box O1 (FOXO1) is a key member of Forkhead Box family, regulating diverse cellular functions during tumor initiation, progression and metastasis. In this review, we focus on recent studies investigating the antineoplastic role of FOXO1 in digestive malignancy. This review aims to serve as a guide for further research and implicate FOXO1 as a potent therapeutic target in digestive malignancy.

1. Introduction According to Global Cancer Statistics from the American Cancer Society (ACS), 167,400 deaths of digestive malignancy are projected to occur in the United States, which might account for more than one quarter of all cancer deaths in 2017 [1]. The lack of early diagnosis tools and effective treatment options is a major contributor to the dismal survival outcome [2,3]. Digestive malignancy mainly includes hepatocellular carcinoma (HCC), colorectal cancer, gastric cancer, pancreatic cancer, esophageal cancer, and oral cancer. Most of these malignancies progress quickly and chemotherapy is the preferred treatment to prolong the survival of patients. Nevertheless, the available treatment regimens prove to be marginally effective with various unwanted adverse effects [4,5]. Therefore, recent studies have been focused on searching for novel therapeutic medications with a better understanding of drug targets. Accordingly, FOXO1 (Forkhead box O1) has attracted extensive attentions in recent years. FOXO1, also known as the forkhead rhabdomyosarcoma transcription factor (FKHR), belongs to the Forkhead box (FOX) family [6,7]. The first study of FOX family was performed in Drosophila by Weigel and Jäckle [8]. Genetic mutation of Forkhead, the region-specific homeotic gene, leads to abnormal embryonic development [9,10]. Thus fardauer formation-16is the only FOX member has been identified in

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invertebrates (Caenorhabditis elegans) [11]. By contrast, the Fox family contains four members in vertebrates, including FOXO1, FOXO3, FOXO4, and FOXO6 [12]. In normal organ/tissues, both the amino- and C-terminal regions of FOXO1 are essential for the remodeling of linker histones. Members of the ‘O’ class of FOXO are involved in binding regulatory sequences in compacted chromatin, thereby promoting DNA remodeling and binding of other transcription factors [9]. FOXO1 ablation may contribute to defective angiogenesis and embryonic lethal. On the other hand, haploinsufficiency of FOXO1 protects against insulin resistance caused by defective insulin signaling [13]. In addition, loss or reactivation of FOXO1 in humans, as a result of chromosomal deletion (13q14), may promote androgen- and androgen receptor-independent prostate tumorigenesis [1–15]. Previous reviews have provided comprehensive overview of the important roles of FOX1 played in embryonic development and metabolism (REF). In this review, we focus on the emerging role of FOXO1 in the development of digestive malignancies including HCC [14], colorectal cancer [15], gastric cancer [16], pancreatic cancer [17], oral cancer [18], and esophageal cancer [19]. We will highlight the surprising role of this transcription factor in anti-neoplastic actions. Specifically, we will first provide a brief overview of various digestive malignancies and the regulatory mechanism of during digestive malignancy development. We will then introduce roles of FOXO1 in the progression of digestive

Corresponding author. E-mail address: [email protected] (J. She). These authors contributed equally to this work.

http://dx.doi.org/10.1016/j.semcancer.2017.09.009 Received 10 July 2017; Received in revised form 25 September 2017; Accepted 27 September 2017 1044-579X/ © 2017 Published by Elsevier Ltd.

Please cite this article as: Shi, F., Seminars in Cancer Biology (2017), http://dx.doi.org/10.1016/j.semcancer.2017.09.009

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Fig 1. Structure of the transcription factor FOXO1. FOXO1 contains a forkhead DNA-binding domain (FHD), a nuclear export sequence (NES), a nuclear localization signal (NLS), and a transactivation domain (TAD). Sites of phosphorylation, ubiquitination, and acetylation are marked by different colors.

transactivation activity and promotes its phosphorylation, possibly through reducing the DNA-binding capability of the transcription factor [29,30]. Clearance of FOXO1 is dependent on ubiquitination. Ubiquitin-proteasome system (UPS) hydrolyzes pFOXO1. In consistence with this finding, FOXO1 mutation avoids ubiquitination [31–33]. Mutation of FOXO1 where three Akt sites were replaced by alanines in the NLS displays a reduction in ubiquitination. It was postulated that NLS mutation of pFOXO1 promotes its nuclear import, and consequently FOXO1 escapes from ubiquitination [32]. Taken together, the nucleocytoplasmic shuttling of FOXO1 regulated by the three posttranslational modifications is critical for determining cell destiny (Fig. 2).

malignancy where we summarize the antineoplastic mechanisms of FOXO1, including anti-proliferation, anti-progression, and pro-apoptosis effects. Finally, we will discuss the roles of FOXO1 in chemotherapy and its clinical relevance. We will offer different perspectives regarding the still controversial mechanism. This review will highlight recent advances and provides an elaborate picture of FOXO1, which will be helpful in drug design and clinical therapy of digestive malignancy. 2. Roles of FOXO1 in neoplasms 2.1. Regulatory mechanism of FOXO1 FOXO1 is mainly expressed in adipose tissues [12]. FOXO1 contains a forkhead DNA-binding domain (FHD), a nuclear export sequence (NES), a nuclear localization signal (NLS), and a transactivation domain (TAD) [20], which controls the nucleocytoplasmic shuttling of FOXO1 and genes transcription [21] (Fig. 1). Mammalian FOXO1 is regulated by a variety of posttranslational modifications such as phosphorylation, acetylation, and ubiquitination. These modifications are pivotal for regulating the activities of FOXO1. Upon posttranslational modifications, FOXO1 is able to integrate diverse signals to mediate cellular functions such as proliferation, apoptosis, differentiation, DNA repair, and autophagy [22]. In addition, binding of multiple growth factors including insulin to their corresponding receptors leads to activation of FOXO1 and triggers the recruitment and activation of the phosphoinositide kinase (PI3K), which in turn activates several serine/threonine kinases, especially Akt and serum glucocorticoid inducible kinase (SGK) [23]. By contrast, in the absence of insulin or insulin-like growth factor 1 (IGF-1), FOXO1 is localized in the nucleus, where it causes cell cycle arrest and cell death. Intriguingly, insulin and IGF-1 directly activate PI3K/Akt/SGK pathway and inhibit FOXO1, thereby causing cell survival and longevity. IGF-1/ Akt signaling can also induce the nuclear export and promote the phosphorylation of FOXO1, which accelerates the growth of gastric cancer cells [24]. FOXO1 nuclear export is controlled by other proteins, for example 14-3-3. 14-3-3 proteins represent a family of highly homologous proteins in all eukaryotic organisms from Drosophila to human [25]. 14-3-3 proteins bind FOXO1 and accelerate the nuclear export of FOXO1, promoting the formation of phosphorylated FOXO1 (pFOXO1) [26]. In addition, the mTOR signaling inhibitor Rapamycin can also induce the nuclear export of FOXO1, leading to FOXO1 inactivation. The resulting reduced antineoplastic efficacy is partly attributed to the activation of the PI3K/Akt pathway [27]. Moreover, Chung’s group reported that knockdown of recepteur d'Origine nantais (RON) inhibits the phosphorylation of FOXO1 and promotes apoptosis and cell cycle arrest in human colorectal cancer cells [28]. FOXO1 acetylation appears to exert inhibitory effects on its

2.2. FOXO1 and carcinogenesis Carcinogenesis is a pathological alteration of epithelial/mesenchymal cells under the stimulation of carcinogenic factors including inflammation, chemicals, and radiation [34–36]. FOXO1 is a tumor-suppressing factor that inhibits carcinogenesis. Consistently, disruption of FOXO1 levels/activity promotes carcinogenesis. Several major signaling pathways, such as PI3K, mitogen-activated protein kinase (MAPK), and IκB kinase (IKK), promote carcinogenesis through FOXO family members [37]. Previous studies have reported that low levels of FOXO1 are closely associated with digestive malignancy [38,39]. Wang et al. performed differential co-expression analysis of 465 hepatic genes in HCV-cirrhotic patients with and without HCC. They found that FOXO1 plays crucial roles in HCC development and hepatic carcinogenesis by regulating protein synthesis through ribosome, spliceosome and steroid biosynthesis, although the exact mechanisms remain unidentified in their research [40]. In human gastric cancer epithelial cells, pFOXO1 is highly expressed and has a cytoplasmic localization, suggesting that unbalanced distribution of FOXO1 subcellular location might contribute to the pathogenesis of gastric cancer in Helicobacter pylori infected patients [41]. In 272 gastric carcinoma specimens, the cytoplasmic expression of pFOXO1 in tumor cells is observed in 85% specimens. The levels of the protein are positively associated with increased number of CD34-immunopositive microvessels and higher expression of angiogenesis-related proteins, including hypoxia inducible factor-1α (HIF-1α), vessel endothelial growth factor (VEGF), phosphorylated protein kinase B (PKB), and nuclear factor-κB (NF-κB) [42]. Immunohistochemistry analysis showed that pFOXO1 is highly expressed in 298 gastric carcinoma specimens and more likely to be found in the early pTNM stages, suggesting that pFOXO1 is highly correlated with gastric carcinogenesis [43]. MicroRNA (miR) is a conserved class of small, endogenous, non-coding RNA that is capable of regulating gene expression at post-transcriptional levels in diverse cellular processes, including carcinogenesis. The expression of nuclear FOXO1 is low in gastric cancer cells, possibly due to the high expression of 2

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Fig. 2. FOXO1-involved signaling network. A variety of molecules regulate the expression and activity of FOXO1 and are involved in controlling survival of cancer cells.

antineoplastic drug in phase II clinical trials, triggers the Silent Information Regulator 1 (SIRT1)/FOXO1 apoptosis pathway in HCT116 colon cancer cells [60]. Curcumin, a well-known bioactive compound derived from the turmeric [61], induces apoptosis in pancreatic cancer cells through the inhibition of the PI3K/Akt pathway and activation of FOXO1. Curcumin treatment leads to decreased Bcl2/Bax ratio and increased caspase9/3 ratio [62]. Depletion of thep85 subunit of PI3K sensitizes colorectal cancer cells to 5-fluorouracil (5-FU)-induced apoptosis through activating FOXO1. These multiple lines of evidence support that FOXO1 is critical for cell survival, and FOXO1 activation leads tocancer cell apoptosis and reduced tumor growth [63]. Furthermore, reactive oxygen species (ROS) production has also been shown to activate FOXO1 and induce apoptosis of cancer cells, enhancing drug efficacy while reducing drug resistance [64].

miR107 that induces nuclear export and inactivation of FOXO1 [44–46]. Interestingly, Li et al. reported that miR132 also plays a similar role in gastric cancer cells [47]. 2.3. Antineoplastic mechanisms of FOXO1 2.3.1. Proliferation Proliferation is a pathophysiological process characterized by increased cell division and cell growth. Infinite proliferation is a unique feature of neoplasm and may cause immense damage to human body [48–51]. Previous evidence has suggested that FOXO1 inhibits proliferation of different digestive malignancy. Aquaporin 9 (AQP9) is the main aquaglyceroporin in the liver and its expression is downregulated in human HCC. Li et al. reported that overexpression of AQP9 in liver cancer cells inhibits PI3K/Akt pathway to increase levels of FOXO1, thereby restraining cell proliferation. In addition, AQP9 overexpression also increases apoptotic cells as evidenced by caspase-3 immunostaining [52]. Moreover, miR124 overexpression results in inactivation of Akt and activation of FOXO1 through silencing sphingosine kinase 1 (SPHK1) in gastric cancer. MiR124 activation of FOXO1 promotes the expression of cell-cycle inhibitors, leading to decreased cell proliferation [53]. Interestingly, Yang et al. reported that miR1269 is highly expressed in human HCC and promotes the proliferation of HCC through downregulating FOXO1. Consistently, inhibition of miR1269 decreases the proliferation of HCC as shown by increased the percentage of cells at G1/G0 phase. Accordingly, the percent of the cells atS phase are dramatically reduced. They further discovered that the formation of pGL3-FOXO1-3′-untranslated regions (UTR) restrains the activity of FOXO1 [54]. Moreover, depletion of Aurora A kinase by RNA interference (RNAi) in HCC upregulates FOXO1 in a p53-dependent manner, resulting cell cycle arrest. These findings suggest that FOXO1 regulated by Aurora A kinase inhibition is responsible for blockage of HCC proliferation [55]. These studies demonstrate that FOXO1 is a potential anti-proliferation molecule for digestive malignancy.

2.3.3. Progression FOXO1 also exerts its antineoplastic actions by inhibiting tumor progression, which is characterized by differentiation, migration, and invasiveness of tumor cells. HCC is known to be enriched with microvessels with high metastasis capability [65–67]. Leung’s group discovered that increased expression of miR183/96/182 induces the activation of FOXO1 in HCC, leading to reduced number of blood vessels and metastasis. They further discovered that increased levels of FOXO1 inhibit cell differentiation, further blocking HCC progression [68]. Gastric cancer tissues exhibits reduced FOXO1 suppression which enhances the expression of HIF-1α mRNA and proteins resulting in increased angiogenesis and progression of gastric cancer [42]. In addition, FOXO1 expression negatively regulates the migration and invasion of several gastric cancer cell lines (SNU-638, MKN45, SNU-216 and NCI-N87) by downregulating human estrogen receptor 2 (HER2) accompanied by increased expression of E-cadherin. Consistently, FOXO1 knockdown promotes migration and invasion of gastric cancer cells, concomitant with increased expression of HER2 [69]. It was found that FOXO1 silencing enhances angiogenesis of gastric cancer by upregulating HIF-1α and VEGF. In line with this finding, FOXO1 activation reverses these effects and suppresses tumor progression by downregulating SIRT1 [70]. In conclusion, these studies suggest that FOXO1 exerts antineoplastic mechanisms via decreasing cell proliferation and increasing cell apoptosis in digestive malignancy (Fig. 3).

2.3.2. Apoptosis Apoptosis is also referred to as programmed cell death controlled by multiple apoptotic associated genes including Bax. Resisting apoptosis is one of the most prominent hallmarks of neoplasm [56–58]. The development of neoplasm is regarded as a consequence of imbalanced apoptosis versus proliferation [59]. β-Lapachone, a potent 3

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Fig. 3. FOXO1 blocks neoplastic pathogenesis through multiple mechanisms in digestive malignancy. FOXO1 upregulates the levels of caspase and downregulates the levels of Bcl-2. Moreover, FOXO1 blocks cell cycle progression, meanwhile suppressing angiogenesis and enhancing apoptosis.

3. Roles of FOXO1 in diverse human digestive neoplasms

3.2. Colorectal cancer

3.1. HCC

Colorectal cancer, also referred to as bowel cancer, is malignancy developed in the colon or rectum. Previously, miR96 has been shown to be overexpressed in human colorectal cancer [82]. Silencing of miR96 results in inhibiting the proliferation of colorectal cancer cells via activating FOXO1 [83]. Interestingly, miR223 is expressed at low levels in the colorectal cancer cell line HCT116 which shows high levels of pFOXO1 in the cytoplasm [84]. In addition, adenomatous polyposis coli (APC) can activate caveolin-1 and execute its tumor suppression function via FOXO1 at the early stages of colon carcinogenesis [85]. The mTOR inhibitor Rapamycin induces the phosphorylation of FOXO1 and promote tumor growth in colorectal cancer cells. This finding partially explains that Rapamycin treatment renders drug resistance and tumor growth via crosstalking to FOXO1 [27].

HCC, also known as liver cancer, is the primary malignant tumor of the liver and intrahepatic duct [71,72]. An estimated 782,500 new cases and 745,500 deaths occurred worldwide during 2012, with China alone accounting for nearly 50% of the total cases and deaths [73]. FOXO1 plays important roles in hepatocyte proliferation and liver metabolism. MK-801, a glutamate antagonist, dephosphorylates Thr24 of FOXO1 and induces its nuclear import, thus increasing transcription of thioredoxin-interactingprotein (TXNIP) gene, which is concomitant with increased cyclin D1 and G1/S cell cycle arrest [74]. Depletion of Aurora A leads to upregulation of FOXO1 and cell cycle arrest at the G2/M phase in a p53-dependent manner, which corresponds to restrained proliferation of HCC [55]. The oncoprotein Hepatitis B X-interacting protein (HBXIP) inhibits gluconeogenesis by promoting the nuclear exclusion of FOXO1concomitant with increased growth of hepatoma cells [75]. MicroRNAs play a significant role in the development of HCC via FOXO1 signaling and FOXO1 repression is likely to be associated with cancer progression and unfavorable outcome of HCC [76]. For example, FOXO1 levels are higher in HCC patients with a better prognosis (> 3 year survival) than those with a poor prognosis (< 3 year survival) [14]. Hepatitis C virus (HCV) core protein promotes the expression of miR196a and facilitates cell proliferation by inducing the G1-S transition in the HepG2 and Huh 7 cells. However, overexpression of FOXO1 markedly reverses these effects and suppresses the growth of HCC [77]. miR145-induced insulin receptor substrate 1 (IRS1) reduction restrains the phosphorylation of Akt and in turn sustains FOXO1 activity, thereby delaying the progression of HCC [78]. miR135a overexpression increases the migration and invasion of HCC cells through reducing FOXO1 activity. Conversely, miR135a inhibition reverses the effects by increasing the levels of FOXO1 [79]. In addition, Gα12 gep oncogene inhibits FOXO1 following dysregulation of miR135b and miR194, thereby promoting the development of HCC [80]. Moreover, another microRNA miR96 is upregulated in HCC. Inhibition of miR96 significantly represses HCC proliferation and colony formation accompanied by upregulation of FOXO1. In agreement with this finding, inhibition of FOXO1 promotes cell proliferation and colony formation [81]. These results again indicate that increase in the levelsFOXO1may provide beneficial effects for treating HCC.

3.3. Gastric cancer Gastric cancer is the second most common cause of cancer-related death worldwide [41]. miR132 levels are significantly increased in gastric cancer specimens. Interestingly, depletion of miR132 increases the protein levels of FOXO1. Li et al. reported that decreased levels of FOXO1 in leads to significant increase in the proliferation of gastric cancer cell in vitro and in vivo. Conversely, FOXO1 activation by using miR132 significantly decreases the proliferation of colorectal cancer cells. Notably, the group discovered that miR132 decreases the protein levels of FOXO post-transcriptional modification without altering FOXO1 mRNA in gastric cancer cells [47]. High levels of serum IGF-1 and IGF-1 receptor (IGF-1R) are also found in gastric cancer patients. IGF-1/Akt pathway induces nuclear exclusion of FOXO1 and promotes the phosphorylation of FOXO1. These findings suggest FOXO1 downstream of IGF signaling is critical for cell proliferation and apoptosis [24]. Interestingly, enforced expression of miR107 is able to promote cell proliferation in NCI-N87 and AGS gastric cancer cells. Treatment with miR107 antisense oligonucleotides (miR107antisense) blocks tumor growth by downregulating FOXO1. All these findings support that FOXO1 acts as a tumor suppressor in gastric cancer [44]. 3.4. Pancreatic cancer Pancreatic cancer is the fifth leading cause of male death all over the world [73,86–88]. Overexpression of miR21 in pancreatic ductal 4

5

Tissues from Barrett's oesophagus patients HSC-3 and TW206 oral squamous carcinoma

1049 HCC cases and 1052 controls (non-tumor patients)

esophageal cancer Oral cancer

HCC

[12]

[76] [77] Repressed FOXO1 regulated by ZBTB20 is associated with a poor 5-year survival FOXO1a is involved in the early carcinogenesis of colon cancer in FAP patients

GNA13 is closely associated with cancer progression and poor survival by suppressing FOXO1 Gastric cancer

BxPC-3 and Panc-1 cells Pancreatic cancer

130 HCC samples and paired adjacent non-tumor samples 11 healthy clean-colon subjects, 59 patients with colorectal cancer, and 9 FAP patients Gastric tissues from gastric cancer and paired adjacent nontumorous of 426 patients

NCI-N87 and AGS cells

HCC Colorectal cancer Clinical research

[78]

[72] [14]

[37]

[64]

APC may activate caveolin-1 and perform tumor suppressing functions via FOXO1a signaling during early stages of colonic carcinogenesis miR107 promotes cell proliferation while antisense miR107 blocks cell proliferation and tumor growth by downregulating FOXO1 Benzyl isothiocyante induces apoptosis and suppresses pancreatic cancer growth by inhibiting PI3K/AKT and activating FOXO1 signaling, which is correlated with increased expression of Bim, p27, and p21 Akt-related FOXO1 inactivation induces the early carcinogenesis of esophagus Quercetin inhibits EGFR/Akt pathway with a concomitant FOXO1 activation while FOXO1 knockdown attenuates quercetin-induced antineoplastic actions The CT/TT genotype in rs17592236 (FOXO1) and the rs17592236 polymorphism are associated with decreased HCC hereditary susceptibility Gastric cancer

HepG2 cells HCC

HT29-APC and HT29-b-gal cells

HepG2 and HuH-7 cells HCC

Colorectal cancer

[60]

[53]

Models

Apart from digestive malignancy, FOXO1 acts as an anti-neoplastic factor in other cancers. Pan and coworkers discovered that FOXO1 may suppress ERK activation and chemoresistance by disrupting IQGAP1MAPK interaction in prostate cancer cells [96,97]. Cdk5 inhibition induces apoptosis of urinary tumor-initiating cells by stabilizing the transcription factor FOXO1, thereby suppressing its chemoresistance [98]. Moreover, Zhang et al. used the cervical cancer cell line C-33A to investigate the role of FOXO1. The results exhibit that the antitumor factor TNF-α increases the expression levels and transcriptional activity of FOXO1. Furthermore, knockdown of FOXO1 inhibits TNF-α-induced apoptosis and expression of caspase-3, 8, and 9. Collectively, these results suggest that TNF-α upregulates the transcriptional factor FOXO1, contributing to an increased expression of apoptotic genes and tumor apoptosis [99].

Types

3.6. Other neoplasms

Research type

Table 1 Basic and clinical antineoplastic actions of FOXO1 in different DSN.

Evidence

FOXO1 also suppresses the growth and proliferation of other digestive malignancy, such as oral cancer and esophageal cancer. The squamous cell carcinomas of head and neck (SCCHN) with aberrant epidermal growth factor receptor (EGFR) signaling are often associated with poor prognosis and a low survival rate. Studies have revealed that FOXO1 is also important for tumor suppression in both oral and esophageal cancer. For example, Quercetin treatment blocks cell growth by inducing G2 arrest and apoptosis in EGFR-overexpressing HSC-3 and TW206 oral cancer cells. Specifically, Quercetin inhibits EGFR/Akt pathway with concomitant FOXO1 activation while FOXO1 knockdown attenuates quercetin-induced antineoplastic effects. This suggests that FOXO1 is crucial in Quercetin-induced growth suppression of EGFRoverexpressing oral cancer [18]. Caffeic acid phenethyl ester (CAPE) is a bioactive component extracted from propolis. Kuo et al. reported that CAPE treatment suppresses cell proliferation and colony formation of TW2.6 human oral squamous cell carcinoma (OSCC) cells dose-dependently via activating FOXO1 [94]. In addition, Akt is abnormally activated in Barrett's oesophagus with high grade dysplasia and adenocarcinoma, concomitant with increased proliferation and inhibited apoptosis. Sample analysis demonstrated that activation of Akt is associated with pFOXO1, suggesting that Akt-related FOXO1 inactivation is associated with initial malignant changes in the esophagus [95]. Taken together, all of the above mentioned studies have shown that FOXO1 acts as a tumor suppressor for multiple digestive malignancies including HCC, colorectal cancer, gastric cancer, pancreatic cancer, oral and esophageal cancer. Findings from these studies also highlight the possibility for targeting FOXO1 to block digestive malignancy (Table 1).

Basic research

3.5. Oral and esophageal cancer

MK-801 dephosphorylates Thr24 in FOXO1 and induces its nuclear import, thus promoting cyclin D1 and G1/S cell cycle arrest Inhibition of miR96 significantly represses proliferation and colony formation of cancer cells by activating foxo1 while the inhibition of FOXO1 promotes cell proliferation and colony formation

Reference

adenocarcinoma (PDAC) cells decreases FOXO1 protein levels by targeting 3′UTR, whereas inhibition of miR21 increases FOXO1 levels. Moreover, administration of miR21 antisense significantly upregulates FOXO1 levels in implanted PDAC, resulting in significant reduction in PDAC growth. These results highlight the miR21/FOXO1 axis as a therapeutic target for inhibiting the growth of PDAC [89]. Sulforaphane (SFN) restrains cell proliferation and colony formation, and induces apoptosis through caspase-3 signaling in pancreatic cancer. Specifically, SFN suppresses phosphorylation of Akt and extracellular signal-regulated kinase (ERK), which activates FOXO1 and leads to tumor suppression [90]. Similarly, Benzyl Isothiocyante also induces apoptosis and suppress pancreatic cancer growth by activating FOXO1 signaling through inhibiting PI3K/AKT, which is correlated with the increased expression of Bim, p27, and p21 in BxPC-3 cells [17]. Moreover, FOXO1 also suppresses the development of pancreatic cancer under the control of smurf2 ubiquitin ligase [91], arsenic trioxide [92], and resveratrol [93]. These studies provide supports that FOXO1 is a potential drug target for pancreatic cancer which warrants further experiments to confirm.

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4. Prospects and conclusion

from 130 HCC and paired adjacent non-tumor samples and discovered that ZBTB20 promotes proliferation, via ability, and carcinogenesis of HCC, concomitant with low levels of FOXO1. They further reported that decreased levels of FOXO1 and high levels of ZBTB20 are associated with a poor 5-year survival rate [107]. These clinically relevant studies suggest that increase in the levels of FOXO1 is beneficial for DNC treatment. That said, FOXO1 has also been reported to be involved in chemoresistance and oncogenesis in certain types of cancer cells. For example, Cisplatin treatment induces FOXO1 activation in MKN45 and SNU-601 gastric cancer cells, and FOXO1 overexpression increases the cisplatin resistance without changes in cell growth. Conversely, FOXO1 silencing enhances Cisplatin cytotoxicity and Cisplatin-induced apoptosis via activating the PI3K/Akt pathway. Interestingly, further studies revealed that the drug resistance may result from a mutant form of (FOXO1 AAA), which contributes to aberrant activation of FOXO1 (check whether I rephrase it in a right way) [108]. Moreover, Kim et al. reported that expression of pFOXO1a is correlated with reduced tumor growth and a longer survival rate. They suggested that pFOXO1 promotes cell cycle arrest in gastric cancer [109]. Together these findings suggest different functions of pFOXO1 and further research is required for explaining the discrepancy. We proposed a model where FOXO1 serves as an important antineoplastic factor during digestive malignancy development. We overview how FOXO1 is regulated by multiple posttranslational modification including phosphorylation, acetylation, and ubiquitination. These modifications are critical for nuclear shuttling of this transcription factor. Nuclear export or FOXO1 phosphorylation leads to FOXO1 inactivation and cell growth, which is correlated with the development of malignancy in the digestive system. Experimental and clinical evidence further suggests that decreased expression of FOXO1 has a close correlation with incidence of digestive malignancy; high levels of FOXO1 predict an optimal outcome in digestive malignancy patients. We then analyze three main antineoplastic mechanisms, anti-proliferation, antiprogression, and pro-apoptosis in relevance to FOXO1 regulations. Finally, we discuss the roles of FOXO1 in chemotherapy and its clinical relevance. Together these findings suggest sophisticated roles of FOXO1 in digestive malignancy development. Many questions remain regarding the underlying molecular and cellular function of FOXO1. In particular, one would 1) further elucidate the roles of the FOX family members to facilitate the understanding of FOXO1; 2) explore the upstream and downstream molecules and provide a comprehensive picture of FOXO1 signaling network that includes many other players such as Akt, PI3K, HER, IGF-1; 3) accelerating clinical trials of drugs targeting FOXO1 in digestive malignancy in addition to animal model testing.

FOXO1 is able to enhance the efficacy of chemotherapy in digestive malignancy. Therefore endeavors have been made to combine FOXO1 with anti-tumor drugs. For example, although treatment with 5-FU is the first line of therapy for advanced colorectal cancer, effectiveness is often hampered by dose-related drug resistance and toxicity [100]. Interestingly, Pterostilbene activates FOXO1 in Caco-2 colorectal cancer cells, which sensitizes colon cancer cells to 5-FU cytotoxicity and reduces drug resistance, as shown by a significant increase in Caco-2 cells at pre-G phase and increased Bax/Bcl-2 ratio [101]. In addition, Thyroid hormone (TH), a hormone involved in cell metabolism, acts as an anti-apoptosis factor on thyroid hormone receptor (THR)-expressing HCC cells. TH lowers the efficacy of chemotherapy drugs, including cisplatin, doxorubicin, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by downregulating FOXO1, revealing that TH/ THR signaling promotes chemotherapy resistance through downregulating the activity of FOXO1 [102]. These studies demonstrate that FOXO1 is an active factor for enhancing the efficacy and reducing resistance of chemotherapy. FOXO proteins are major targets of insulin action and the role of insulin in FOXO1 expression/activity remains a hotspot in recent research. O-Sullivan et al. built liver-specific insulin receptor knockout (LIRKO) and IR/FoxO1 double knockout (LIRFKO) mice models. They discovered that LIRKO is correlated with low expression of FOXO1 and both hepatic glucose production (HGP) and glucose utilization is impaired in LIRKO mice, and these defects are also restored in LIRFKO mice. They conclude that inhibition of FoxO1 might lead to insulin resistance (IR) and metabolic dysregulation [103]. Wang et al. discovered that IR of skeletal muscle cells is governed by pancreatic cancer-derived exosomes through the insulin-mediated PI3K/Akt/ FOXO1 signalling pathways, which indicate that FOXO1 is a potential target of insulin action and glucose metabolism [104]. Abundant clinical evidence has confirmed the antineoplastic roles of FOXO1 in digestive malignancy. For example, Agostini’s group analyzed the serum samples from 11 healthy clean-colon subjects, 59 patients with colorectal cancer, and 9 patients with adenomatous polyposis (FAP). They found that the level of FOXO1a is dramatically decreased in FAP group as compared to healthy people, indicating that downregulation of FOXO1a is involved in early carcinogenesis of colon cancer [105]. Additionally, Calvisi and colleagues analyzed HCC tissues from patients with better (< 3 years survival) and poorer prognosis (> 3 years survival). They discovered that ubiquitination and proteasome degradation of FOXO1 inhibits cell cycle, contribute to HCC progression, and is correlated with a better outcome [14]. (I don’t understand this. Look like contradict what you described). Moreover, Tan et al. conducted a hospital-based study and include 1049 HCC cases and 1052 controls (non-tumor patients). They examined whether polymorphism of miR-targeting sites in FOXO1 is correlated with HCC susceptibility. Intriguingly, three miR-targeted UTR sites of FOXO1 (rs17592236), FOXO3 (rs4946936), and FOXO4 (rs4503258) were identified. Multivariate logistic regression analysis (MLRA) showed that the CT/TT genotype in rs17592236 and the rs17592236 polymorphism are associated with decreased HCC hereditary susceptibility [106]. Moreover, in another study Zhang et al. examined 426 gastric cancer samples and paired adjacent non-tumorous gastric tissues to determine correlation between the oncogenic protein Guanine nucleotide binding protein alpha 13 (GNA13) and FOXO1. Patients were followed every 3 months for the first year and every 6 months for the next 2 years, and finally annually. The study showed that upregulation of GNA13 expression promotes the proliferation and carcinogenesis of cancer cells by suppressing FOXO1. Further research showed that GNA13 is markedly overexpressed in cancer tissues and closely associated with cancer progression and a poor survival rate. [16]. Zinc finger BTB domaincontaining 20 (ZBTB20) is a member of the POK family and it is significantly overexpressed in HCC. Kan and colleagues analyzed samples

Conflict of interest The authors declare that there is no conflicts of interest. Acknowledgements This work was supported by International Cooperation Program of Shaanxi Province, China (No. 2016KW-004); the Clinical Research Award of the First Affiliated Hospital of Xi’an Jiaotong University, China (No. XJTU1AF-CRF-2015-029); NIH (Nos. R01DK100342, R01DK113144 and R01HL132996) References [1] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics 2017, CA Cancer J. Clin. 67 (1) (2017) 7–30. [2] D. Lieberman, et al., Screening for colorectal cancer and evolving issues for physicians and patients: a review, J. Am. Med. Assoc. 316 (20) (2016) 2135–2145. [3] M.C. Arkan, Cancer Fat and the fate of pancreatic tumours, Nature 536 (7615) (2016) 157–158. [4] F. Loupakis, et al., Initial therapy with FOLFOXIRI and bevacizumab for metastatic

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