Elsevier

Peptides

Volume 158, December 2022, 170892
Peptides

Insulin-like growth factor 1 serum levels in different stages of gastric cancer and their association with Helicobacter pylori status

https://doi.org/10.1016/j.peptides.2022.170892Get rights and content

Highlights

  • A high serum level of IGF-1 and H. pylori can increase the risk of gastric tumors.

  • H. pylori may lead to higher serum IGF-1 levels.

  • In gastric cells, H. pylori and IGF-1 can induce PI3K/Akt-mTOR and Ras/Raf/ERK pathways.

  • Inhibiting H. pylori and IGF-1 may be a new therapeutic target in gastric tumors.

Abstract

High serum insulin-like growth factor 1 (IGF-1) and positive Helicobacter pylori (H. pylori) may increase the risk of gastric cancer (GC). We aimed to investigate IGF-1 serum levels in different stages of GC patients and their association with H. pylori status. A total of 90 participants, including 60 GC patients and 30 noncancerous (NC) individuals, were included in the present study. IGF-1 serum levels and candidate proteins were assessed using enzyme-linked immunosorbent and immunohistochemistry techniques. Likewise, Giemsa staining was applied to detect H. pylori infection. The candidate genes' expression, including IGF-1R, PI3KCA, AKT1, mTOR1, KRAS, BRAF, and ERK1, was also evaluated by a real-time PCR assay. The results of advanced GC stages indicated a significantly high IHC score for IGF-1R and phosphorylated AKT, mTOR, and ERK proteins compared to the early stages. Moreover, IGF-1 serum levels and the expression of candidate genes were considerably increased in the advanced GC patients compared to the early stages and the positive H. pylori status compared to the negative H. pylori status (P < 0.05). As a result, high IGF-1 serum levels and positive H. pylori status may be correlated with gastric tumor progression, and the inhibition of IGF-1 and the eradication of H. pylori infection might be new therapeutic targets in GC patients.

Graphical Abstract

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H. pylori-CagA can promote or inhibit vital proteins in oncogenic or tumor suppressor signaling pathways via several molecular mechanisms. It promotes signal transduction pathways and inflammatory responses via these signaling pathways in gastric epithelial cells. It also induces nuclear factor-κB (NF-κB) and cytokines, which are mediated by the Janus kinase/signal transducers and activators of transcription (Jak/Stat) that, in turn, can trigger IGF-1 expression and inflammatory signaling pathways. IGF-1 can also be promoted by pro-inflammatory cytokines, including IL-6, IL-8, IL-1β, and TNF-α. In this setting, IGF-1 actives PI3K/Akt/mTOR and Ras/Raf/ERK signaling pathways and NF-κB expression, leading to cell proliferation, invasion, migration, and cancer progression.

Introduction

Gastric cancer (GC) is considered the fifth most common malignancy and the fourth most lethal cause of cancer worldwide [1], [2]. Nearly a million new cases of GC are identified, and over 700,000 people die of this disease yearly [3]. Most GC patients are diagnosed at the end stage, resulting in a poor prognosis and a narrow range of therapeutic alternatives [4]. Some studies on gastric cells have revealed the importance of growth factors, like insulin-like growth factor 1 (IGF-1), in tumorigenesis and cancer development [5]. The high circulating IGF-1 may increase the risk of colorectal, pancreatic, gastric, prostate, and esophageal cancers. It can facilitate metastasis due to cell migration and invasion [6]. The interaction between IGF-1 and IGF-1R can activate two main signaling pathways: phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of the rapamycin (mTOR) and RAS/RAF/the extracellular signal-regulated kinase (ERK). These pathways regulate cellular processes, including cell proliferation, differentiation, and apoptosis [7], [8].

Additionally, the elevated level of IGF-1 was related to less tumor differentiation, a high stage, metastasis, and positive Helicobacter pylori (H. pylori) status [9], [10], [11]. In this setting, H. pylori infection is the most critical risk factor that dysregulates two main signaling pathways; PI3K/AKT/mTOR and RAS/RAF/ERK, which are involved in gastric cancer development [12], [13]. It is one of the primary etiological factors associated with antral gastritis and has been categorized as a Class 1 carcinogen by the World Health Organization [14], [15]. The studies showed that interaction between H. pylori and IGF-1 might enhance GC development, so its eradication can decrease serum IGF-1 levels [16], [17]. In persistent infections, H. pylori can further increase the risk of inflammation and, finally, non-cardia gastric adenocarcinoma [18]. The constant inflammation by H. pylori can induce the release of pro-inflammatory cytokines, which can modify the secretion and the biological functions of IGF-1 [19]. Therefore, the present study aimed to assess IGF-1 serum levels and the expression of candidate genes in the different stages of GC patients and their association with H. pylori status.

Section snippets

Study population

A total of 90 tissue samples, including 60 tumors from gastric cancer (GC) patients and 30 non-tumor gastric mucosae from noncancerous (NC) individuals, were used in the present study. All participants were admitted to Rasool Akram Hospital, Tehran, Iran, from October 2016 to October 2018. The samples were extracted using endoscopy procedures. They were diagnosed based on histopathological examinations according to the tumor–node–metastasis (TNM) staging system [20]. The NC individuals with

Clinicopathological data

The demographic and clinicopathological information are shown in Table 2. The mean age of the GC and the NC participants was 56.2 ± 11.5 and 54.4 ± 12.6 years, of which 44 (73.2%) and 17 (56.6%) were men, and 16 (26.8%) and 13 (43.4%) were women, respectively. Moreover, 41 (69.6%) and 13 (43.3%) participants of the GC and NC groups were positive for H. pylori status, respectively. Other clinical factors, including tissue location, cell differentiation, TNM staging, tumor invasion depth, lymph

Discussion

Our findings showed IGF-1 serum levels and the candidate proteins were meaningfully increased in the advanced GC stages compared to the early ones. Likewise, their levels were significantly higher in GC patients with positive H. pylori than the negative H. pylori status. So, IGF-1 and H. pylori infection may be therapeutic targets in GC patients.

Many studies have shown that the abnormal expression of IGF-1 could be used as a valuable biological marker for early diagnosis and treatment

Conclusion

As a result, high IGF-1 serum levels and positive H. pylori status were associated with advanced GC patients. Although signaling mechanisms of GC progression caused by high IGF-1 levels and H. pylori infection have not been fully revealed, IGF-1 inhibition and H. pylori eradication might be new therapeutic targets. However, further studies are needed to find the best strategy for GC treatments.

Acknowledgment

This study was co-funded by the Tehran University of Medical Sciences (Grant Number: 29025) and the Iran University of Medical Sciences (Grant Number: 26256).

Author contributions

FG: manuscript preparation, sample collection, processing, and data analysis. AMA: study conception and design and article revision. SA: clinical annotation and sample collection. SI: article revision. MM: sample collection, diagnostic of histological and sample processing.

Conflict of interest

The manuscript authors have no conflicts of interest to declare and

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  • 1

    Ali Mohammad Alizadeh and Shahram Agah contributed equally to this work.

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