Tumor microenvironment (TME) plays an active role in promoting tumor progression. To further understand the communication between TME and tumor cells, this study aimed at investigating the involvement of CD44, a type I cell surface receptor, in the crosstalk between tumor cells and TME. We have previously shown that chondroitin sulfate proteoglycan serglycin (SRGN), a CD44-interacting factor, was preferentially secreted by cancer-associated fibroblasts (CAFs) for promoting tumor growth in breast cancer patients. In this study, we show that SRGN is overexpressed in primary non-small cell lung cancers (NSCLCs), by both carcinoma and stromal cells. Using gain-of-function and loss-of-function approaches, we show that SRGN promotes NSCLC cell migration and invasion as well as colonization in the lung and liver in a CD44-dependent manner. SRGN induces lung cancer cell stemness, as demonstrated by its ability to enhance NSCLC cell sphere formation via Nanog induction, accompanied with increased chemoresistance and anoikis-resistance. SRGN promotes epithelial-mesenchymal transition by enhancing vimentin expression via CD44/NF-κB/claudin-1 (CLDN1) axis. In support, CLDN1 and SRGN expression are tightly linked together in primary NSCLC. Most importantly, increased expression of SRGN and/or CLDN1 predicts poor prognosis in primary lung adenocarcinomas. In summary, we demonstrate that SRGN secreted by tumor cells and stromal components in the TME promotes malignant phenotypes through interacting with tumor cell receptor CD44, suggesting that a combined therapy targeting both CD44 and its ligands in the TME may be an attractive approach for cancer therapy.
Gain of function of membrane receptor was a good strategy exploited by cancer cells to benefit own growth and survival. Overexpression of HER2 has been found to serve as a target for developing trastuzumab to treat 20-25% of breast cancer. However, little or none of the other membrane receptor was found to be useful as a potential target for breast cancer treatment since then. Here, we showed that amplified signaling of interleukin-17 receptor B (IL-17RB) and its ligand IL-17B promoted tumorigenicity in breast cancer cells and impeded acinus formation in immortalized normal mammary epithelial cells. External signal transmitted through IL-17RB activated nuclear factor-κB to upregulate antiapoptotic factor Bcl-2 and induced etoposide resistance. Elevated expression of IL-17RB had a stronger correlation with poor prognosis than HER2 in breast cancer patients. Interestingly, breast cancer patients with high expression of IL-17RB and HER2 had the shortest survival rate. Depletion of IL-17RB in trastuzumab-resistant breast cancer cells significantly reduced their tumorigenic activity, suggesting that IL-17RB and HER2 have an independent role in breast carcinogenesis. Furthermore, treatment with antibodies specifically against IL-17RB or IL-17B effectively attenuated tumorigenicity of breast cancer cells. These results suggest that the amplified IL-17RB/IL-17B signaling pathways may serve as a therapeutic target for developing treatment to manage IL-17RB-associated breast cancer.
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