Le Han, Shuo Chen, Shi-Yu Du

Abstract Inositol polyphosphate-4-phosphatase type II (INPP4B) is a newly discovered PI(3,4,5)P3 phosphatase.Many studies have revealed that INPP4B is upregulated or downregulated in tumors of the digestive system, and the abnormal expression of INPP4B may be attributed to the occurrence, development, and prognosis of tumors of the digestive system.This paper reviews studies on the correlations between INPP4B and digestive system tumors and the roles of INPP4B in the development of different tumors to provide a theoretical basis for further research on its molecular mechanism and clinical application."INPP4B” and “tumor" were searched as key words in PubMed and in the CNKI series full text database retrieval system from January 2000 to August 2023.A total of 153 Englishlanguage studies and 30 Chinese-language studies were retrieved.The following enrollment criteria were applied: (1) Studies contained information on the biological structure and functions of INPP4B; (2) studies covered the influence of abnormal expression of INPP4B in digestive system tumors; and (3) studies covered the role of INPP4B in the diagnosis, treatment, and prognosis of digestive system tumors.After excluding the literature irrelevant to this study, 61 papers were finally included in the analysis.INPP4B expression is low in gastric cancer,colon cancer, pancreatic cancer, and liver cancer but it has high expression in esophageal cancer, colon cancer, pancreatic cancer, and gallbladder cancer.INPP4B is involved in the occurrence and development of digestive system tumors through the regulation of gene expression and signal transduction.The abnormal expression of INPP4B plays an important role in the development of digestive system tumors.Studies on INPP4B provide new molecular insights for the diagnosis, treatment, and prognosis evaluation of digestive system tumors.

Key Words: Inositol polyphosphate-4-phosphatase type II; Tumors of the digestive system;Protein kinase B; Serum and glucocorticoid-regulated kinase 3

INTRODUCTION

Tumors of the digestive system, including esophageal cancer, stomach cancer, colorectal cancer, liver cancer, pancreatic cancer, and gallbladder cancer, have high morbidity and mortality rates in China and abroad.According to the 2020 global cancer statistics released byCA:A Cancer Journal for Clinicians[1,2], the top five cancers in the world were breast,lung, colorectal, prostate, and stomach cancers, and the top five cancers in China were lung, colorectal, stomach, breast,and liver cancers.Lung, colorectal, liver, stomach and breast cancers rank as the top five in terms of mortality worldwide,and lung, liver, stomach, esophageal, and colorectal cancers rank as the top five in terms of mortality in China.Thus, the diagnosis and treatment of digestive tumors at home and abroad are still important issues since these cancers seriously endanger the lives and health of people worldwide.The pathogenesis of digestive tumors is complex, and the risk factors are numerous.There are few early screening and diagnosis techniques for these tumors; in addition, the treatment response of patients with late-stage disease is poor, and the metastasis rate is high.In recent years, studies have found that inositol polyphosphate-4-phosphatase type II (INPP4B) is underexpressed or overexpressed in a variety of digestive system tumors and that it can regulate the gene expression and transcription of tumor cells, thus playing an important role in tumor inhibition or promotion.

To provide a theoretical basis and new ideas for the study of digestive system tumors, the correlation between INPP4B and digestive system tumors and the corresponding molecular mechanisms related to the occurrence and development of digestive system cancers are reviewed in this paper (Table 1).

Structure of INPP4B

INPP4B is a newly discovered PI(3,4,5)P3 phosphatase independent of Mg2+.Its gene is located at 4q31.21 of chromosome 8[3,4].The molecular weight is approximately 110 kDa.INPP4B is highly expressed in human skeletal muscle, breast,heart, brain, liver, pancreas, and prostate tissues[5].The INPP4B structure consists of three parts: An N-terminal C2 Lipid binding domain, NHR2, and a C-terminal phosphatase domain.Among them, the C2 Lipid binding domain and the Cterminal phosphatase domain can bind to PI(3,4,5)P3.The C-terminal phosphatase domain contains the conserved sequence of amino acids 842-849 (CKSAKDRT), including the catalytic active site C(X)5R, which leads to the phosphorylation of lipids and proteins.INPP4B can dephosphorylate the D4 phosphate group of PI(3,4)P2 and degrade it to PI(3)P, thereby inhibiting protein kinase B (AKT) activation[4-8].

Effects of INPP4B in digestive system tumors

At present, there are different experimental conclusions on the relationship between INPP4B and tumors.In a variety of malignancies, such as breast cancer of the reproductive system[9], hepatocellular carcinoma (HCC) of the digestive system[10], prostate cancer of the urinary system[11], and leukemia of the blood system[12], INPP4B has a high frequency of decreased expression, and this phenotype is often closely related to a poor prognosis in patients.The decrease in INPP4B is particularly pronounced in some highly metastatic tumors, such as highly metastatic colorectal cancer[13].This suggests that INPP4B may play an anticancer role in tumor tissues.However, in estrogen-receptor-positive breast cancer[14],BCR/ABL1fusion gene-positive acute myeloid leukemia[15], pancreatic ductal adenocarcinomas[16], and other types of tumors, INPP4B overexpression can promote the development of tumors.This indicates that INPP4B may play a role in promoting tumor progression.As a result, INPP4B may have dual and complex effects on tumors.

In tumors of the digestive system, INPP4B mainly functions through the phosphoinositide 3-kinase/protein kinase B(PI3K/AKT) and PI3K/serum and glucocorticoid-regulated kinase 3 (PI3K/SGK3) pathways.

INPP4B and PI3K/AKT:The PI3K/AKT signaling pathway is closely related to cell proliferation and apoptosis.Extracellular stimulation can activate PI3K, and the downstream factor of PI3K (AKT) can be phosphorylated and activated by the combination of the PH domain with PI(3,4,5)P3 or PI(3,4)P2, thus triggering the proliferation and apoptosis of regulated cells.INPP4B can be generated by activating PI3K to produce PI(3,4)P2.PI(3,4)P2 is furtherhydrolyzed to PI(3)P, which blocks the PI3K/AKT signal, thus affecting downstream signaling.Therefore, INPP4B has a significantly negative regulatory effect on the PI3K/AKT signaling pathway, thus inhibiting the proliferation of tumor cells.Therefore, INPP4B has become a potential tumor suppressor of the PI(3,4,5)P3 phosphatase family (Figure 1A)[3-7,17].However, other studies have come to a different conclusion: The overexpression of INPP4B can promote cancer by promoting the expression of AKT[18-20].This process may be related to the expression of phosphate and tensin homolog deleted on chromosome 1/PI3K/AKT (PTEN/PI3K/AKT).PTEN is an analog of INPP4B.PTEN also regulates PI3K/AKT to promote cell proliferation[21,22].Some researchers believe that overexpression of INPP4B inhibits the expression of PTEN and activates the PI3K/AKT pathway, which plays a role in promoting cancer (Figure 1B)[18-20].Therefore,through the PI3K/AKT pathway, INPP4B may play both anticancer and procancer roles.

Table 1 Role of inositol polyphosphate-4-phosphatase type II in tumors of the digestive system

INPP4B and PI3K/SGK3:Aside from AKT, SGK is another serine/threonine protein kinase family.There are three isoforms of the SGK family: SGK1, SGK2, and SGK3.These three isoforms are highly homologous with AKT and share a common substrate specificity.The SKG3 protein has an approximately 55% sequence similarity with AKT.The hydrolytic product of INPP4B, PI(3)P, can bind to and activate SKG3[23,24].Activation of the PIK3/SGK3 signaling pathway may enhance the growth, proliferation, and migration of tumor cells[23-25].The overexpression of INPP4B in tumor cells may promote the occurrence and development of tumors and resist the process of apoptosis of tumor cells by activating the PIK3/SGK3 signaling pathway (Figure 2)[18,26].INPP4B is highly expressed in PIK3CA-mutant breast cancer.Breast cancer with oncogenic PIK3CA mutations activates SGK3 signaling while inhibiting AKT, thus mediating the proliferation of estrogen-receptor-positive breast cancer cells[9,26].Overexpression of INPP4B through the activation of SGK3 to play a role in promoting cancer has also been found in melanoma[27,28].Therefore, INPP4B plays a role in promoting cancer in tumor cells through the PIK3/SGK3 pathway.

The above studies confirm that INPP4B is closely related to the occurrence and development of cancers through the PIK3/AKT and PIK3/SGK3 signaling pathways.INPP4B may play a role in inhibiting or promoting cancer in different tumor cells, which may be related to its effect on different signaling pathways.

INPP4B AND GASTRIC CANCER

Gastric cancer is one of the most common malignant tumors of the digestive system.Early diagnosis relies on invasive examination, such as gastroscopy.Gastric cancer is highly malignant, invasive, and metastatic.At present, the study of INPP4B in gastric cancer is still in the preliminary stage.

INPP4B is downregulated in gastric cancervsnormal tissues.Huet al[29] used quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) to detect the expression of INPP4B mRNA and protein in the cancer tissues and adjacent tissues of 50 patients with gastric cancer, respectively.The results of qRT-PCR revealed that the mRNA expression ofINPP4Bin gastric cancer tissues was significantly lower than that in paracancerous tissues (P＜0.01).The results of IHC revealed the positive rate of INPP4B protein expression in gastric cancer tissues was significantly lower than that in paracancerous tissues (28.0%vs82.0%,P＜ 0.01).Moreover, INPP4B mRNA and protein expression are considered to be related to the differentiation degree, lymph node metastasis, and tumor-node-metastasis (TNM) stage of gastric cancer (P＜ 0.01).Fan[30] used qRT-PCR and IHC to determine the expression of INPP4B in gastric cancer tissues,normal tissues, and tumor-adjacent tissues and the expression of AKT and phosphorylated AKT (p-AKT) in 36 patients.The expression of INPP4B in cancer tissues was significantly lower than that in normal tissues and paracancerous tissues.Moreover, the expression of AKT and p-AKT in cancer tissues was significantly higher than that in normal tissues and paracancerous tissues (P＜ 0.001).INPP4B was negatively correlated with AKT and p-AKT (P＜ 0.001).Therefore, INPP4B plays a role as a tumor suppressor in gastric cancer.Decreased INPP4B expression activates the phosphorylation of AKT,which leads to the occurrence and development of gastric cancer.

Figure 1 Molecular mechanism of inositol polyphosphate-4-phosphatase type II in cancer proliferation through the phosphoinositide 3-kinase/protein kinase B pathway.A: Phosphoinositide 3-kinase can activate cell membrane receptors, which increases the content of PI(3,4,5)P3 and PI(3,4)P2.PI(3,4,5)P3 and PI(3,4)P2 further bind and activate the downstream factor protein kinase B (AKT).Activation of AKT promotes cell proliferation and ultimately tumor development.Inositol polyphosphate-4-phosphatase type II promotes the conversion of PI(3,4)P2 to PI(3)P, thereby reducing the content of PI(3,4,5)P3 and PI(3,4)P2, which inhibits the AKT pathway; B: Phosphate and tensin homolog deleted on chromosome 10 can reduce the content of PI(3,4,5)P3 and PI(3,4)P2 by dephosphorylating PI(3,4,5)P3 into PI(4,5)P2, thereby inhibiting the AKT pathway.INPP4B was found to inhibit PTEN, which resulted in increased intracellular PI(3,4,5)P3 and PI(3,4)P2.PI(3,4,5)P3 and PI(3,4)P2 activate the AKT pathway, leading to the proliferation of tumor cells.INPP4B: Inositol polyphosphate-4-phosphatase type II; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; PTEN: Phosphate and tensin homolog deleted on chromosome 10.

Figure 2 Molecular mechanism of inositol polyphosphate-4-phosphatase type II in cancer proliferation through the phosphoinositide 3-kinase/serum and glucocorticoid-regulated kinase 3 pathway.PI(3)P, produced by inositol polyphosphate-4-phosphatase type II, can bind to and activate serum and glucocorticoid-regulated kinase 3, which promotes the occurrence and development of tumors and resists the process of apoptosis of tumor cells.INPP4B:Inositol polyphosphate-4-phosphatase type II; PI3K: Phosphoinositide 3-kinase; SGK3: Serum and glucocorticoid-regulated kinase 3.

Yanget al[31] used qRT-PCR and ELISA to determine the mRNA and protein expression levels of INPP4B in peripheral blood samples from 50 patients with gastric cancer and 30 healthy volunteers, respectively.The mRNA and protein expression levels of INPP4B in the peripheral blood of gastric cancer patients were significantly lower than those in the blood of healthy volunteers (P＜ 0.05).Moreover, the mRNA and protein expression levels of INPP4B in the peripheral blood of gastric cancer patients were correlated with TNM stage, lymph node metastasis, and infiltration depth (P＜ 0.05),and the sensitivity and specificity values were 78.0% and 84.0%, respectively.Liet al[32] also found that the positive rate of INPP4B protein expression in gastric adenocarcinoma tissues (21.43%) was lower than that in tumor-adjacent tissues(83.57%), and the difference was statistically significant (P＜ 0.01).The expression levels of INPP4B protein in gastric adenocarcinoma tissues were negatively associated with lymph node metastasis, differentiation degree, and TNM stage(P＜ 0.01).The survival time of the INPP4B high-expression group was significantly longer than that of the lowexpression group.A total of 79 patients with advanced gastric cancer and 40 healthy people were selected for analysis of the expression ofINPP4BmRNA in peripheral blood in the research of Liu Zet al[33].They found that the relative expression ofINPP4BmRNA in the study group was lower (P＜ 0.05); among patients with low mRNA expression ofINPP4B, the proportion of patients with stage IV gastric cancer was higher than that of patients with stage IIIB (P＜ 0.05).Compared to that in the treatment-sensitive group, the expression ofINPP4BmRNA in the treatment-resistant group was lower, and the expression ofPI3KandAKTmRNA was higher (P＜ 0.05).The median survival time of the highexpression group was also longer than that of the low-expression group (P= 0.006).Therefore, the expression of INPP4B mRNA and protein in gastric cancer tissues and peripheral blood may become an effective molecular index to indicate progression, facilitate early diagnosis, and predict prognosis in gastric cancer patients.

Recently, IHC andin situhybridization studies of EBER expression were used to assess the cancer tissues and paracancerous tissues of 301 patients with gastric cancer; these studies showed that the expression of INPP4B protein was decreased in most gastric cancer tissues infected with Epstein-Barr virus (EBV) compared to those not infected (P＜ 0.05)[34].According to the gastric cancer typing in the 2014 American Cancer Genome Atlas Research Network[35], EBVpositive gastric cancer is often considered to have a poor prognosis, and this type of gastric cancer is characterized by more extensive DNA hypermethylation, PIK3CA mutation, PD-L1/2 overexpression, andCDKN2Agene silencing.In this type of gastric cancer, INPP4B protein is hypermethylated by EBV, which further explains the pathogenesis and poor prognosis of EBV nucleic acid-positive gastric cancer.Yuenet al[36] used RT-PCR, methylation-specific PCR, and other experimental techniques to find that in EBV-infected nasopharyngeal carcinoma tissues, the downregulation of INPP4B protein was closely related to the hypermethylation of theINPP4Bpromoter region.The latent membrane protein 1 of EBV changes the methylation state of the host genome by inducing the methyltransferase activity of the host cell, which may indicate the mechanism[37,38].Moreover, Maet al[39] discovered that before treatment of EBV-positive and EBVnegative gastric cancer cell lines with methylation inhibitors, the methylation level of CpG islands in the promoter region of theINPP4Bgene was decreased, and the transcription and expression levels of theINPP4Bgene were increased.CpG island methylation in the promoter region is one of the important mechanisms ofINPP4Bgene inactivation, and methylation inhibitor treatment can promote the transcription and expression of theINPP4Bgene in EBV-positive and EBV-negative gastric cancer cell lines[39].Therefore, the downregulated expression ofINPP4B, an anticancer gene in gastric cancer[34] and nasopharyngeal carcinoma[36], is related to EBV infection-mediated hypermethylation of theINPP4Bpromoter region.These preliminary studies provide new research directions regarding the mechanism by which EBV infection causes nasopharyngeal carcinoma and gastric cancer.

However, a study showed thatINPP4Bmay play dual roles as an oncogene and tumor suppressor gene in different tissue grades and clinical stages[40].

Using gastric cancer cells, Wuet al[40] found that knockdown of INPP4B in BGC-823 cells could increase the apoptosis rate, decrease cell migration capability, and suppress proliferation and colony formation, while overexpression of INPP4B in AGS cells had opposite effects, suggesting thatINPP4Bis an oncogene in gastric cancer cells.Usingin vitroanalyses of gastric cancer cells, Wuet al[40] discovered that downregulation of INPP4B in BGC-823 cells resulted in an elevation of the apoptosis rate, a reduction in cell migration capability, and inhibition of proliferation and colony formation.Conversely, upregulation of INPP4B in AGS cells exhibited contrasting effects, indicating its oncogenic role in gastric cancer cells.Mechanistically, INPP4B overexpression increased the level of phosphorylated SGK3 (p-SGK3) in AGS cells,while INPP4B knockdown increased the p-AKT level in BGC-823 cells.Wu[41] also found that INPP4B was positively correlated with cytoplasmic hypoxia inducible factor-1A (HIF-1A) (P= 0.003), which might affect the microvessel density and the occurrence of tumors.Hence, the roles of INPP4B in the prognosis of gastric cancer patients may be paradoxical.

In summary,INPP4Bis thought to act as an oncogene by regulating AKT in gastric cancer.INPP4B plays a negative regulatory role in the occurrence, development, invasion, and metastasis of gastric cancer.Downregulation of INPP4B expression has been associated with EBV infection.The detection of INPP4B mRNA and protein expression in peripheral blood or cancer tissues has appreciated guiding significance for the determination of cancer subtypes and prognosis.The identification of INPP4B as a potential therapeutic target suggests its promising role in the management of gastric cancer.

INPP4B AND CONLON CANCER

Colon cancer is a common malignancy of the digestive system.The early diagnosis of colon cancer depends on colonoscopy and other invasive examinations, and the prognosis is usually poor.The in-depth study of INPP4B and colon cancer may provide a new direction for early diagnosis, treatment, and prognosis judgment in this malignancy.

Role of INPP4B in inhibiting colon cancer

Sunget al[42] determined the expression of INPP4B in the colorectal cancer cell lines HCT-116, SW620, DLD-1, and WiDr by RT-PCR, Western blot, and IHC.INPP4B expression levels were significantly reduced in colorectal cancer cell lines (P＜ 0.001).Choiet al[43] studied the expression of INPP4B in colorectal cancer tissues in the public genome database and discovered that the expression level of INPP4B was significantly reduced in colorectal cancer.Studies by Maet al[44] have shown that the downregulation of INPP4B can lead to a decrease in p27 expression and an increase in cyclin D1 expression in colorectal cancer cells, thus promoting the occurrence and development of the tumors.This supports thatINPP4Bacts as an anticancer gene in colon cancer.One of the upstream regulatory signals of INPP4B is miR-1290 (P＜0.05).MiR-1290 may inhibit the expression of INPP4B by binding to the 3'-untranslated region ofINPP4Band thus promote the proliferation of colorectal cancer (P＜ 0.05)[44].Therefore, the above research indicates thatINPP4Balso plays a role as a tumor suppressor gene in colon cancer.

Role of INPP4B in promoting colon cancer

However, some studies have shown that high expression of INPP4B in colon cancer may have a carcinogenic effect.Guoet al[18] used IHC to detect INPP4B expression in 124 pairs of colon cancer and tumor-adjacent tissues.INPP4B was upregulated in more than half of the cancer tissues (P＜ 0.01).This may be due to an increase in the transcription ofINPP4Bin colon cancer cells mediated by E26 transformation-specific 1 (Ets-1).The overexpression of INPP4B promoted the development and progression of colon cancer by promoting the expression of AKT and SGK3.The study also found that the activation of AKT and SGK3 was blocked by silencing INPP4B (P＜ 0.05), thereby inhibiting the proliferation of colon cancer cells and delaying the growth of xenograft tumors of colon cancer.Ruanet al[19] found that INPP4B promoted colorectal cancer by activating the mTORC1 signaling pathway and cap-dependent cAMP-activated protein (P＜ 0.05).This process was also found to be associated with increased AKT and SGK3 expression (P＜ 0.05).High INPP4B expression in colon cancer is often accompanied by high SGK3 expression, which explains why INPP4B appears to promote cancer in some colon cancers[18,45].Therefore, the PI3K/SGK3 pathway may be the pathwayviawhich INPP4B plays a role in promoting colon cancer.

Previous results also indicate that INPP4B overexpression in colon cancer activates AKT[18,19].A similar phenomenon in which INPP4B overexpression leads to increased AKT expression has also been found in esophageal cancer[20].Therefore, the carcinogenic effect of INPP4B in colon cancer and other digestive system tumors may also be related to the activation of the PI3K/AKT pathway.Some studies suggest that this process may be related to the interaction between INPP4B and PTEN[18,46,47].Guoet al[18] found that the increase in INPP4B expression was accompanied by the downregulation of PTEN in colon cancer cells, while the upregulation of PTEN was observed in INPP4B knockout cells.Therefore, overexpression of INPP4B leads to activation of PI3K/AKT in colon cancer cells, which may be related to downregulation of PTEN (P＜ 0.05).

Croftet al[42] reported a new small transcript variant ofINPP4B(INPP4B-S).INPP4B-Sdiffers from full-lengthINPP4B(INPP4B-FL) in that a new small exon is inserted between its 15th and 16th exons, and exons 20-24 are deleted.INPP4B-Swas found to promote the proliferation of colon and breast cancer cells (P＜ 0.01).This suggests that INPP4B may have different isoforms.Different isoforms of INPP4B may have different procancer or anticancer effects and thus may affect the differences in the degree of malignancy and prognosis of tumors.In addition, Chen[48] found that the expression levels of IRF-2 and INPP4B in colorectal cancer tissues were positively correlated and that INPP4B may be involved in the development of microsatellite instability in colorectal cancer.This suggests that there may be other mechanisms for the carcinogenic effects of INPP4B.

These results suggest that INPP4B may be a carcinogenic driver of colon cancer.Therefore, INPP4B could potentially serve as a novel therapeutic target for colon cancer treatment.

Dual function of INPP4B in colon cancer

Recently, Yanget al[13] confirmed the dual role of INPP4B in colorectal cancer in animal experiments.This effect may be attributed to the regulation of Sox2 and Nanog expression by the PTEN/PI3K/AKT signaling pathway.The team used qRT-PCR to find that the expression of INPP4B was decreased in primary colorectal cancer (P＜ 0.05), accompanied by the overexpression of Recombinant Sex Determining Region Y Box Protein 2 (Sox2) and Nanog (P＜ 0.05).In metastatic colorectal cancer, the expression of INPP4B was increased (P＜ 0.05), while antagonism between Sox2 and Nanog and INPP4B was observed (P＜ 0.05).It is suggested that the expression of INPP4B is closely related to the origin of colon cancer.

In summary, the dual role of INPP4B in colon cancer has been demonstrated.This dual function may be related to the PI3K/AKT and PI3K/SGK3 pathways or to the existence of different subtypes of INPP4B.The specific mechanism needs further research and discussion.

INPP4B AND PANCREATIC CANCER

Pancreatic cancer is a kind of digestive system malignancy with high mortality.Pancreatic cancer is characterized by its difficult early diagnosis, high drug resistance rate, and poor prognosis.At present, the study of INPP4B in pancreatic cancer is in the preliminary stage.

Role of INPP4B in inhibiting pancreatic cancer

At present, there are few studies on the role of INPP4B in pancreatic cancer.The INPP4B level in pancreatic cancer cells(ASPC-1, BXPC-3, SW1990, and PANC-1) was significantly reduced compared to that in normal controls, as detected by using Western blot and qRT-PCR (P＜ 0.05).Overexpression of INPP4B inhibited the activation of AKT signaling and partially reversed epithelial-mesenchymal transition (EMT) in pancreatic cancer cells (P＜ 0.05) to reduce invasion[49].Therefore,INPP4Bis a tumor suppressor gene in pancreatic cancer.In addition, the expression of INPP4B and E-cadherin(Ecad) in pancreatic cancer tissues was found to be consistent to a certain extent by using gene overexpression and interference techniques (P＜ 0.05).This process is related not only to the inhibition of AKT expression (the activation of AKT can reduce the expression level of Ecad) but also to the direct effect of INPP4B on Ecad[16,49].A study of 39 primary pancreatic ductal cell adenocarcinoma specimens surgically removed found that INPP4B was involved in the endocytosis and circulation of Ecad[16].A reduction in the level of INPP4B resulted in the loss of Ecad.The loss of Ecad is often the first step of epithelial-mesenchymal transformation in tumorigenesis[50].Therefore, the decrease in INPP4B expression initiated the development of pancreatic cancer.In addition, although the methylation inhibitor failed to reverse the methylation state of theINPP4Bgene promoter region in cancer cells, it upregulated the expression of INPP4B and Ecad (P＜ 0.05)[16].Therefore, the identification of methylation inhibitors that can be effectively employed in clinical settings may represent a novel avenue of research on the treatment of pancreatic cancer characterized by low INPP4B and Ecad expression.Furthermore, an in-depth exploration into the underlying mechanism is warranted.

Role of INPP4B in promoting pancreatic cancer

However, recent studies have collected INPP4B expression data in pancreatic cancer tissues and normal tissues in Gene Expression Profiling Interactive Analysis.Statistical analysis revealed that the expression level of INPP4B in pancreatic cancer tissues was significantly increased (P＜ 0.05).INPP4B downregulation inhibited the proliferation of pancreatic cancer cells, promoted cell apoptosis, and reduced the phosphorylation level of AKT (P＜ 0.05).INPP4Bhas been identified as a significant oncogene in pancreatic cancer.INPP4B can be considered a potential diagnostic marker and independent prognostic marker and may even be a new therapeutic target for pancreatic cancer[51].

Above all, the role of INPP4B in pancreatic cancer is controversial.The controversial point is also related to the regulatory effect of INPP4B on AKT.Similar to colon cancer studies, other studies have found that decreased PTEN expression in pancreatic cancer leads to increased phosphorylation of AKT, which promotes the proliferation of pancreatic cancer cells[52].Therefore, the specific mechanism by which PTEN is involved in the regulatory effect of INPP4B on AKT may be the focus of future studies in pancreatic cancer.

INPP4B AND LIVER CANCER

Liver cancer is the second most common cause of cancer-related death in China, and HCC accounts for approximately 90% of primary liver cancer cases.HCC is often caused by viral hepatitis, alcoholism, nonalcoholic fatty liver disease, and aflatoxin exposure.HCC is difficult to diagnose early and is highly invasive, with a poor overall prognosis and low survival rate.At present, the specific role of INPP4B in liver cancer has not been fully studied.

Zhanget al[53] used IHC to detect the expression of INPP4B and PTEN in 74 Liver cancer tissues, 74 paracancerous tissues, and 30 normal liver tissues.The expression levels of INPP4B and PTEN in liver cancer tissues were significantly decreased (P＜ 0.05), and their expression levels were positively correlated (P= 0.000).INPP4B and PTEN are closely related to the occurrence, development, invasion, and metastasis of liver cancer, and they have obvious antitumor effects and synergistic effects in liver cancer.However, the specific mechanism is not completely clear[53,54].

Xieet al[10] assessed eight HCC cell lines (Hep3B, Huh7, HepG2, HCCC-9810, BEL-7402, QGY-7703, MHCC97L, and MHCC97H) and eight surgically excised specimens and found that miR-765 was highly expressed in HCC.MiR-765 promoted the proliferation and development of HCC.The results of the dual-luciferase reporter and Western blot assays showed that the high expression of miR-765 inhibited the expression of INPP4B (P＜ 0.05).Therefore, INPP4B is a target of miR-765.By inhibiting the expression of INPP4B, miR-765 Leads to upregulation of p-AKT and cyclin D1 and downregulation of phosphorylated forkhead box O3 (p-FOXO3a) and p21 in HCC, thus promoting the development of HCC[55].In the latest research, Tanget al[56] used qRT-PCR and Western blot to determine INPP4B elevation in both metastatic and nonmetastatic HCC samples of 86 human HCC patients (P＜ 0.001).The positive rate of INPP4B expression in metastatic HCC tissues was higher than that in primary HCC tissues.INPP4B was negatively correlated with AKT and p-AKT in HCC cells (P＜ 0.05).This suggests that INPP4B plays an antitumor role in HCC by inhibiting the PI3K/AKT pathway and that INPP4B inhibits the metastasis and invasion of HCC by inhibiting the EMT process of HCC.

Therefore, it is currently believed that INPP4B plays an anticancer role in HCC mainly by inhibiting the PI3K/AKT pathway.The signaling pathway mechanism of INPP4B in HCC is the next research focus.MiR-765 and INPP4B may be new targets for the diagnosis and treatment of HCC.

INPP4B AND ESOPHAGEAL CANCER

There is only one study on INPP4B in esophageal cancer.High expression of INPP4B mRNA and protein in esophageal squamous carcinoma (P＜ 0.05) was found by qRT-PCR and IHC, respectively.INPP4B was positively correlated with the expression of AKT and pAKT in esophageal cancer (P= 0.000).This suggests that high expression of INPP4B may play a role in promoting esophageal cancer[20].Since the role of NPP4B in esophageal cancer has been poorly studied, this conclusion needs to be further confirmed with more research.

INPP4B AND GALLBLADDER CANCER

There are only two studies on INPP4B in gallbladder cancer (GBC) from Wuet al[57].Wuet al[57] found that INPP4B was upregulated in human GBC tissues compared with normal gallbladder tissues, but INPP4B was highly expressed in highly-moderately differentiated GBC and was not associated with the overall survival of GBC patients (P= 0.071).In GBC-SD cells, overexpression of INPP4B increased the expression levels of p-SGK3 and p-Akt, and interference with INPP4B decreased the expression levels of p-SGK3 and p-Akt.In SGC996 cells, overexpression of INPP4B enhanced the expression level of p-SGK3.These results suggest that INPP4B plays an oncogenic role in GC cells and GBC cells and may affect their biological functions through different signaling pathways in different GBCs.In GBC cells, INPP4B knockdown inhibited proliferation, colony formation, migration, and invasion, while INPP4B overexpression had opposite effectsin vitro.These findings suggest that INPP4B may play a dual role in GBC.

CONCLUSION

In summary, INPP4B plays different roles in a variety of digestive system tumors.INPP4B plays an obvious anticancer role in a variety of digestive system cancers, such as gastric cancer, colon cancer, pancreatic cancer, and liver cancer.However, INPP4B is also believed to have promoting roles in colon, pancreatic, and esophageal cancers.The roles of INPP4B in digestive system tumors mainly include the following: (1) EBV and microRNAs can regulate the expression of INPP4B; (2) INPP4B can regulate PI3K/AKT to exert an anticancer effect and can also promote the procancer effect of PI3K/AKT by affecting PTEN; (3) INPP4B can regulate PI3K/SGK3 to promote cancer; and (4) INPP4B can affect the EMT process of some tumor cells.

At present, the understanding of the role of INPP4B in digestive system tumors is still superficial.There are still few studies on its mechanism of action, clinical development, and application in different digestive system tumors.Based on the contradiction and duality shown in current INPP4B research, further research and discussion may be needed regarding the upstream and downstream pathways of INPP4B and the mechanism of action of various subtypes of INPP4B.Future studies should aim to determine its role in promoting or inhibiting cancer in different types of digestive tumors and further consider whether it is possible for it to be clinically detected and applied for treatment by assessing,blocking, or promoting the expression of INPP4B.INPP4B has been found to be associated with drug resistance and radiation resistance in malignant tumors such as ovarian, laryngeal, and lung cancers[58-61].At present, there is a lack of relevant research on this aspect in digestive tumors.In addition, the correlation of INPP4B expression with the features of other digestive system tumors, such as gastrointestinal pancreatic neuroendocrine tumors and tumors in the bile duct,duodenum, and ileum, remains unknown.With the development of this area of research, broad prospects may emerge for the use of INPP4B in the early diagnosis, monitoring, prognosis assessment, and treatment of digestive system malignancies.

ACKNOWLEDGEMENTS

We would like to give our heartfelt thanks to all the people who have helped us with this paper.Our sincere appreciation goes first to China-Japan Friendship Hospital.

FOOTNOTES

Author contributions:Han L contributed significantly to conceptualization, data analysis, and manuscript preparation; Du SY and Chen S helped perform data analysis with constructive discussions; all authors read and approved the final version of the manuscript.

Supported bythe China-Japan Friendship Hospital Foundation, No.2019-1-QN-2.

Conflict-of-interest statement:The authors declare that they have no competing interests to disclose.

Open-Access:This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

Country/Territory of origin:China

ORCID number:Le Han 0000-0002-7591-0805; Shuo Chen 0000-0002-2808-2787.

S-Editor:Yan JP

L-Editor:Wang TQ

P-Editor:Yan JP