Podoplanin is upregulated in the invasive front of oral squamous cell carcinoma (OSCC). Carcinoma-associated fibroblasts (CAFs) may mediate podoplanin expression. However, the role of podoplanin in OSCC cell and fibroblast interaction remains elusive. In the present study, we found that positive podoplanin expression in OSCC cells correlated with smooth muscle actin (α-SMA) expression in CAFs. Using CAFs and normal mucosal fibroblasts (NFs), we established indirect and direct co-culture systems mimicking the structure of OSCC. Podoplanin-overexpressing OSCC cells promoted NF activation; in direct co-culture, but not in indirect co-culture, podoplanin-overexpressing OSCC cells increased fibroblast invasion via matrix metalloproteinase 2 (MMP-2), MMP-14, and αv/β6 integrin receptor (ITGA5/ITGB6) signaling. CAFs also induced podoplanin expression through the transforming growth factor-β1 (TGF-β1)/Smad pathway. TGF-β1 increased the podoplanin-dependent activation of epidermal growth factor receptor (EGFR), AKT, and extracellular signal-regulated kinase (ERK) signaling. Additionally, CAFs promoted OSCC cell invasion by upregulating MMP-2 and MMP-14 expression in both indirect and direct co-culture. Taken together, our findings indicate that podoplanin regulates the interaction between OSCC cells and CAFs via the mutual paracrine effects of TGF-β1.

Tyrosine phosphatase SHP2, encoded by PTPN11, has been implicated in many physiologic and pathologic processes in neoplastic progression. However, controversies are emerging from many studies, indicating SHP2 has a dual role in different types of tumors. We aimed to explore the role of SHP2 in progression and prognosis of colorectal cancer (CRC). SHP2 inhibited CRC cell proliferation and migration, and the phosphorylation of STAT3 was negatively regulated by SHP2 in CRC. SHP2 and nuclear STAT3 were examined in 270 CRC tissues. SHP2 was significantly correlated with nuclear STAT3 (Spearman’s rho = −0.408, P ≤ 0.001). Based on Cox regression analysis, patients with high levels of SHP2 and low levels of nuclear STAT3 had longer disease-specific survival (DSS) (HR, 0.362; 95% CI, 0.165–0.794) and disease-free survival (DFS) (HR, 0.447; 95% CI, 0.227–0.877). Further, low levels of SHP2 and high levels of nuclear STAT3 were independently associated with adverse outcomes in the whole cohort (DFS; HR, 2.353; 95% CI, 1.199–4.619). These results suggest that combination of SHP2 and nuclear STAT3 is a strong prognostic predictor in CRC.

The aims of this study were to investigate the expression levels of β-catenin, Pin1 and cyclin D1 in salivary adenoid cystic carcinomas (SACC ) and to evaluate its clinical importance, furthermore, to elucidate whether β-catenin expression was aberrant in SACC and whether Pin1 was involved in aberrant β-catenin and cyclin D1 expression. The expression of Pin1, β-catenin and cyclin D1 were examined in the specimens of 65 patients with SACC by immunohistochemistry, protein and mRNA expressions were detected by western blotting and RT-PCR in four SACC cell lines. Pin1 was overexpressed in 51 cases of SACC (78%), and high levels of Pin1 expression correlated with cyclin D1 positive expression (p=0.02). Fourteen (22%) cases showed positive immunoreactivity for β-catenin protein in the nuclear/cytoplasmic fraction in tumor tissues, which was defined as cytoplasm/nucleus staining, among which quite evident nuclear expression of β-catenin was detected in six cases (9%), while cyclin D1 positive expression was detected in 41 cases of SACC (63%). Reduced membranous expression of β-catenin was detected in the cases with metastasis (11/14). Theses results suggest that Pin1 and Wnt signalling pathway are activated in SACC and may play a pivotal role in SACC carcinogenesis and metastasis.