Chronic TGF beta stimulation promotes the metastatic potential of lung cancer cells by Snail protein stabilization through integrin beta 3-Akt-GSK3 beta signaling

Chronic exposure to TGFβ, a frequent occurrence for tumor cells in the tumor microenvironment, confers more aggressive phenotypes on cancer cells by promoting their invasion and migration while at the same time increasing their resistance to the growth-inhibitory effect of TGFβ. In this study, a transdifferentiated (TD) A549 cell model, established by chronically exposing A549 cells to TGFβ, showed highly invasive phenotypes in conjunction with attenuation of Smad-dependent signaling. We show that Snail protein, the mRNA expression of which strongly correlates with a poor prognosis in lung cancer patients, was highly stable in TD cells after TGFβ stimulation. The increased protein stability of Snail in TD cells correlated with elevated inhibitory phosphorylation of GSK3β, resulting from the high Akt activity. Notably, integrin β3, whose expression was markedly increased upon sustained exposure to TGFβ, was responsible for the high Akt activity as well as the increased Snail protein stability in TD cells. Consistently, clinical database analysis on lung cancer patients revealed a negative correlation between overall survival and integrin β3 mRNA levels. Therefore, we suggest that the integrin β3-Akt-GSK3β signaling axis plays an important role in non-canonical TGFβ signaling, determining the invasive properties of tumor cells chronically exposed to TGFβ.

GalNAc-T14 promotes metastasis through Wnt dependent HOXB9 expression in lung adenocarcinoma

While metastasis, the main cause of lung cancer-related death, has been extensively studied, the underlying molecular mechanism remains unclear. A previous clinicogenomic study revealed that expression of N-acetylgalactosaminyltransferase (GalNAc-T14), is highly inversely correlated with recurrence-free survival in those with non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism(s) has not been determined. Here, we showed that GalNAc-T14 expression was positively associated with the invasive phenotype. Microarray and biochemical analyses revealed that HOXB9, the expression of which was increased in a GalNAc- T14-dependent manner, played an important role in metastasis. GalNAc-T14 increased the sensitivity of the WNT response and increased the stability of the ß-catenin protein, leading to induced expression of HOXB9 and acquisition of an invasive phenotype. Pharmacological inhibition of ß-catenin in GalNAc-T14-expressing cancer cells suppressed HOXB9 expression and invasion. A meta-analysis of clinical genomics data revealed that expression of GalNAc-T14 or HOXB9 was strongly correlated with reduced recurrence-free survival and increased hazard risk, suggesting that targeting ß-catenin within the GalNAc-T14/WNT/HOXB9 axis may be a novel therapeutic approach to inhibit metastasis in NSCLC.

Factors associated with diffuse-type histology in non-cardia gastric cancer.

<p>Factors associated with diffuse-type histology in non-cardia gastric cancer.</p

Study patients and their classification into groups according to their serum anti-<i>Helicobacter pylori</i> IgG antibody (Hp-IgG) titer.

<p>Study patients and their classification into groups according to their serum anti-<i>Helicobacter pylori</i> IgG antibody (Hp-IgG) titer.</p

The proportion of diffuse-type non-cardia gastric cancer (GC) in each Hp-IgG titer group according to age, sex, and smoking status.

<p>(a) Age: the proportion of diffuse-type GC was highest in the patients aged 30–49 years and decreased with advancing age (<i>p</i><0.001). (b) Age and sex: this difference between age groups was significant in all Hp-IgG titer groups in female. (c) Smoking status: Among the non-smokers, the proportion of diffuse-type GC increased in the higher Hp-IgG titer groups (<i>p</i><0.001).</p

Comparisons between the serum anti-<i>H</i>. <i>pylori</i> IgG (Hp-IgG) titer groups.

<p>Comparisons between the serum anti-<i>H</i>. <i>pylori</i> IgG (Hp-IgG) titer groups.</p

Characteristics of non-cardia gastric cancer with a high serum anti-<i>Helicobacter pylori</i> IgG titer and its association with diffuse-type histology

<div><p>Background</p><p>Data on implications of a high positive titer of serum anti-<i>Helicobacter pylori</i> antibody on gastric cancer (GC) is limited. This study aimed to investigate the characteristics of GC with a high serum anti-<i>H</i>. <i>pylori</i> IgG (Hp-IgG) titer, and its association with diffuse-type GC.</p><p>Methods</p><p>We analyzed clinical and histological characteristics of 917 non-cardia GC patients who underwent gastrectomy. <i>H</i>. <i>pylori</i> infection was determined serologically by measuring Hp-IgG titer with immunoassay. Seropositive patients were divided into three groups (low-positive, mid-positive, and high-positive) according to the Hp-IgG titer value. Tumors were classified according to the Lauren criteria as diffuse or intestinal types.</p><p>Results</p><p>The median age of the patients was 59.0 years, and 33.8% were female. The patents were grouped as follows: seronegative, 188 (20.5%); low-positive, 288 (31.4%); mid-positive, 290 (31.6%); and high-positive 151 (16.5%). The high-positive group was significantly younger (median age, 55.0 years), with a higher proportion of female (45.0%) and non-smokers (58.9%). The proportion of diffuse-type GC increased in the order low-, mid-, and high-positive groups (<i>p</i><0.001). In univariate analysis, the factors associated with diffuse-type GC were younger age, female sex, non-smokers, and a high-positive Hp-IgG titer. Younger age, female sex, and non-smokers remained significant on multivariate analysis whereas the high-positive Hp-IgG titer showed only a tendency toward the association (<i>p</i> = 0.078).</p><p>Conclusions</p><p>Non-cardia GC patients with a high Hp-IgG titer have distinct clinicopathologic characteristics. A high-positive Hp-IgG titer should be interpreted together with patients’ age, sex, and smoking status.</p></div