CD147 mediates transforming growth factor-ß1-induced epithelial-mesenchymal transition and cell invasion in squamous cell carcinoma of the tongue.

Epithelial-mesenchymal transition (EMT) is a physiological process in which epithelial cells attain the motile and invasive characteristics of mesenchymal cells, which results in the development of increased migratory and invasive cell behavior, serving as a vital mechanism of cancer progression. Hence, controlling the EMT for cancer treatment, including head and neck squamous cell carcinoma (HNSCC), is imperative. Among EMT-associated factors, transforming growth factor-ß (TGF-ß) is a well-established potent inducer. Recent research has revealed that CD147, a member of the immunoglobulin superfamily, promotes the EMT. However, the role of CD147 in the EMT and the following tumorigenicity in HNSCC has not been completely elucidated. This study aims to investigate the role of CD147 in the EMT and related tumorigenicity in HNSCC. The present study used two HNSCC cell lines, SAS and FaDu, for in vitro studies. In HNSCC cells, TGF-ß1 induced spindle-shaped morphological changes, and western blot analysis revealed that TGF-ß1 induced changes in EMT markers, downregulation of vimentin, and upregulation of E-cadherin, yet increased CD147. In addition, TGF-ß1 increased cell migration in HNSCC cells. However, a TGF-ß1-induced alteration in EMT makers was attenuated with CD147 silencing by small interfering RNA (siRNA) in SAS cells. In addition, the TGF-ß1-induced cell invasion of SAS was attenuated with CD147 silencing. In conclusion, the present study suggests that CD147 mediates TGF-ß1-induced EMT and tumorigenicity in HNSCC. Hence, CD147 may serve as a vital therapeutic target in HNSCC.

PLEKHN1 promotes apoptosis by enhancing Bax-Bak hetro-oligomerization through interaction with Bid in human colon cancer.

The anti-apoptotic nature of cancer cells often impedes the effects of anti-cancer therapeutic agents. Multiple death signals influence mitochondria during apoptosis, and though many studies have attempted to elucidate these complicated pathways, Bax oligomerization, an important step in the process, remains controversial. Here we demonstrate that pleckstrin-homology N1 (PLEKHN1), also known as cardiolipin phosphatidic acid binding protein, plays pro-apoptotic roles during reactive oxygen species (ROS)-induced apoptosis. Human PLEKHN1 was expressed in several cancer cell lines of differing origin. Its expression was regulated by hypoxia, and it existed in the mitochondrial fraction. Genome editing of hPLEKHN1 in human colon cancer HT-29 cells revealed enhanced survival of knockout cells compared with that of parental cells in vitro and in vivo. Thapsigargin or hydrogen peroxide treatment activated multiple death signals including JNK, Bcl-2 family members, and caspases. PLEKHN1 was bound to Bid, a pro-apoptotic protein, and not to Bax, and PLEKHN1 could remove Bid from transient Bid-Bax complexes. Fluorescent time-lapse imaging revealed that PLEKHN1 aggregated with Bid during thapsigargin- or hydrogen peroxide-induced apoptosis prior to Bax aggregation. Inhibition of PLEKHN1 led to attenuation of Bax-Bak hetero-oligomerization and Bid translocation. The immunohistochemistry of cancer patient specimens showed that PLEKHN1 expression was absent from cancer region at the transition area of normal/cancer tissues. Collectively, the silencing of PLEKHN1 may be the key that cancer cells acquire the drug resistance.

CD147 expression correlates with lymph node metastasis in T1-T2 squamous cell carcinoma of the tongue.

Cervical lymph node metastasis causes a poor prognosis in cases of stage T1-T2 squamous cell carcinoma (SCC) of the tongue. Recent studies have reported that cluster of differentiation (CD)147, also known as extracellular matrix metalloproteinase inducer, contributes to tumor progression. The present study evaluated the role of CD147 in the tumorigenesis of SCC of the tongue in vitro, as well as the association between CD147 expression and cervical lymph node metastasis in clinical samples of SCC of the tongue. Tongue SCC cell lines were used to evaluate in vitro tumorigenesis. In addition, 41 patients with clinical stage T1-T2 tongue SCC were assessed with a histopathological analysis. Univariate and multivariate analysis were performed to investigate the risk of cervical lymph node metastasis associated with histopathological findings. In the in vitro study, cell invasiveness was upregulated by S100 calcium-binding protein A9 (S100A9) stimulation and downregulated following CD147-blocking antibody treatment. The univariate and multivariate analyses identified CD147 expression in the invasive tumor front as an independent risk factor for metastasis. It was concluded that CD147 induces tongue carcinoma cell invasion through its interaction with S100A9. Thus, an evaluation of the extent of CD147 expression in cancer cell nests at the invasive tumor front may help in predicting cervical lymph node metastasis in patients with clinical N0 T1-T2 tongue SCC.

Agr2 mediates paracrine effects on stromal fibroblasts that promote invasion by gastric signet-ring carcinoma cells.

Agr2 is a disulfide isomerase residing in the endoplasmic reticulum (ER), which physiologically regulates protein folding and mediates resistance to ER stress. Agr2 is overexpressed in adenocarcinomas of various organs, where it participates in neoplastic transformation and metastasis, therefore acts as a pro-oncogenic protein. Besides its normal localization in the ER, Agr2 is also found in the serum and urine of cancer patients, although the physiological significance of extracellular Agr2 is poorly understood. In this study, we demonstrated that extracellular Agr2 can activate stromal fibroblasts and promote fibroblast-associated cancer invasion in gastric signet-ring cell carcinoma (SRCC), where Agr2 is highly expressed. Agr2 secreted from SRCC cells was incorporated by the surrounding gastric fibroblasts and promoted invasion by these cells. In turn, activated fibroblasts coordinated the invasive behavior of fibroblasts and cancer cells. Our findings suggested that Agr2 drives progression of gastric SRCC by exerting paracrine effects on fibroblasts in the tumor microenvironment, acting also to increase the growth and resistance of SRCC cells to oxidative and hypoxic stress as cell autonomous effects.