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Liu et al. Th17 activation by H. pylori and triglyceride

INTRODUCTION expression. Interestingly, the local Th17-associated
gastric inflammation results in increased IL-17A in
Gastric cancer (GC) is currently the third leading blood and causes adipose inflammation in HFD-
cause of cancer-related death worldwide due to the fed obese mice. In turn, fat-derived IL-6 and leptin
highly metastatic property and poor prognosis. [1,2] can promote gastric Th17 expansion, thus forming
The overall 5-year survival rate of GC patients is a positive loop in Th17 activation. These findings
only between 15 to 35%. Epidemiological studies suggest that Th17 and IL-17A play a critical role in
[3]
show that persistent Helicobacter pylori (H. pylori) the synergy of Helicobacter infection and metabolic
infection accounts for approximate 75% of confound abnormalities in accelerating GC progression. In
risk factors for GC. [4-6] Understanding the underlying present study, we used clinical GC specimens
mechanism of GC development associated with H. to document Th17-related cytokines and explore
pylori infection will be important for developing novel the roles of H. pylori infection and lipid metabolic
therapeutic methods. disorders in GC development. Our results suggest
that dysregulated lipid metabolism may synergize
H. pylori, a gram-negative spiral-shaped pathogenic with H. pylori to promote GC development.
bacterium, specifically colonizes and induces
damage to the gastric epithelium leading to chronic METHODS
gastritis, ulcers and even cancer. [2,7,8] Considerable
studies have demonstrated that a mixed response Clinical specimens
of Th1 and Th17 cells plays a critical role in H. Forty-two GC specimens were randomly collected
pylori-induced inflammatory gastric diseases and from Fujian Provincial Cancer Hospital in China.
cancer. [9,10] The phenotypes of T helper subsets are H. pylori infection was clinically diagnosed and
determined by the local cytokine milieu and their confirmed with the expression of CagA, VacA or
lineage-specific transcription factors. [11-13] H. pylori [22,23]
elicits Th1 response to produce interferon-γ and both. The patients were also divided into high
and normal lipid groups with a diagnostic cut-off of
tumor necrosis factor-α causing chronic gastritis and [24]
ulcers. [9,13] Th17 cells are also frequently recruited by 1.7 mmol/L of plasma triglyceride (TG). All tumors
H. pylori to the gastric mucosa, and are characterized were histological diagnosed according to the World
by expression of interleukin (IL)-17A/F, granulocyte- Health Organization classification. The pathological
macrophage colony-stimulating factor (GM-CSF), TNM stage and clinical stages were also recorded. [25]
IL-21, IL-22 and IL-23, and the transcription factor of Extraction of RNA and quantitative real-time
RORγt. [11,14] While activation of Th17 cells contributes
to bacterial eradication, Th17-mediated immune- PCR
[15]
response can be detrimental to gastric epithelium Total RNA was extracted using Triazol kit (Invitrogen
during gastritis. [9,14] Th17 cells can be further activated Company, USA) with slight modifications of protocol.
in tumor microenvironment due to involvement of The RNA was reverse transcribed using Hifair™ III
IL-6 and transforming growth factor-β. [16,17] Although 1st Strand cDNA Synthesis Kit (Yesen Company,
activation of Th17 cells might have antitumor activity China). The cDNAs were then used in quantitative
by facilitating the recruitment of other effector immune polymerase chain reaction (qPCR) quantitative
cells, Th17-derived IL-17A favors angiogenesis analysis of IL-6, leptin, IL-17A, GM-CSF, CXCL1 and
[18]
and tumor growth through inducing IL-6 that in turn RORγt mRNA expression levels in ABI 7500 system
activates STAT3 signaling to promote tumor survival (Applied Biosystems, Foster, CA) by using Hieff™
®
and angiogenesis. [19,20] qPCR SYBR Green Master Mix (Yesen Company,
China). Their relative levels were normalized to β-actin
It has been reported that obesity and diabetes can expression. Specific primers used in this study were
worsen the process of Helicobactor-associated listed in Table 1.
GC. [19,21] However, the cross-talk between
Helicobactor infection and metabolic disorders in Statistical analysis
the gastric carcinogenesis remains not completely Data analysis was conducted by using Graph pad
understood. We recently demonstrated that high 6.0 Software. After log transformation, normal
fat diet (HFD) and obesity could strongly enhance distribution was analyzed. Comparison between the
H. felis-induced GC in mice. [19] We observed that two groups was done using t-test and Spearman
H. felis infection potently stimulates stomach Th17 analysis of correlation was performed between the
recruitment and development, and enhanced groups. The contingency were analyzed by using
mobilization of bone-marrow derived IMCs via CXCL1 Chi-square testing.
170 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ August 29, 2017