Abstract
BackgroundTumor chemo-resistance is a hallmark of malignant tumors as well as the major cause of poor survival rates in lung cancer. Transmembrane-4 L-six family member-1 (TM4SF1), an antigen that serves as an oncogene, mainly affects tumor invasion and metastasis. We investigated the roles of TM4SF1 in non-small-cell lung cancer progression, particularly in the regulation of chemo-sensitivity.MethodsTM4SF1 was silenced by small interfering RNA transfection.TM4SF1 expression in cell lines and tissues were determined by Quantitative Real-time PCR. MTS, clonogenic, Transwell assay, Flow cytometry verified cell function. By RT-PCR, Western blot, the mechanisms were studied.ResultsTM4SF1 was upregulated in both lung cancer cell lines and tissues, compared with 293 T epithelial cells. Analysis of online databases revealed that high expression of TM4SF1 is associated with the older patient age, smoking habits, and poor patient survival and outcome. Knockdown of TM4SF1 substantially inhibited tumor cell growth, migration, and invasion, and enhanced the chemo-sensitivity of the lung cancer cell lines A549 and H1299 to cisplatin and paclitaxel. Furthermore, the silencing of TM4SF1 induced lung cancer cell apoptosis and arrested cells at the G2/M phase. These results suggest that TM4SF1 is associated with lung cancer progression and appears to be required for tumor cell growth, maintenance of chemo-resistance and metastasis. We further found that TM4SF1 exerts these effects in part by regulating the expression of the discoidin domain receptor DDR1 and its downstream target, the Akt/ERK/mTOR pathway, and consequently alters cell sensitivity to chemo-reagents and contributes to invasion and metastasis.ConclusionsThese findings demonstrate that TM4SF1 may serve as a prognostic factor for lung cancer chemo-response and patient outcome.
Highlights
Tumor chemo-resistance is a hallmark of malignant tumors as well as the major cause of poor survival rates in lung cancer
With RT-PCR, we identified that Transmembrane-4 L-six family member-1 (TM4SF1) was up-regulated in the lung cancer cell lines A549, H1299, H1650, H460, H446, and H1466, compared with the epithelial cell 293 T cells (Fig. 1d upper panel), suggesting that it may potentially promote lung cancer
RT-PCR was further used to confirm the TM4SF1 expression in five pairs of lung tumor tissues and non-tumor tissues (Fig. 1d lower panel). These findings together demonstrated that TM4SF1 is up-regulated in both lung cancer cell lines and tumor tissues, and it may be a potentially related to lung cancer progression
Summary
Tumor chemo-resistance is a hallmark of malignant tumors as well as the major cause of poor survival rates in lung cancer. We investigated the roles of TM4SF1 in non-small-cell lung cancer progression, in the regulation of chemo-sensitivity. Data from more than 1300 patients enrolled in eight trials of adjuvant cisplatin-based therapy have indicated a 5% survival benefit at 5 years. These disappointing results are partially due to the chemo-resistance of NSCLC [3]. Understanding the mechanisms of how NSCLC becomes resistant to chemo-reagents is crucial
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