Extracellular serglycin upregulates the CD44 receptor in an autocrine manner to maintain self-renewal in nasopharyngeal carcinoma cells by reciprocally activating the MAPK/β-catenin axis.
Serglycin is a proteoglycan that was first found to be secreted by hematopoietic cells. As an extracellular matrix (ECM) component, serglycin promotes nasopharyngeal carcinoma (NPC) metastasis and serves as an independent, unfavorable NPC prognostic indicator. The detailed mechanism underlying the roles of serglycin in cancer progression remains to be clarified. Here, we report that serglycin knockdown in NPC cells inhibited cell sphere formation and tumor seeding abilities. Serglycin downregulation enhanced high-metastasis NPC cell sensitivity to chemotherapy. It has been reported that serglycin is a novel ligand for the stem cell marker CD44. Interestingly, we found a positive correlation between serglycin expression and CD44 in nasopharyngeal tissues and NPC cell lines. Further study revealed that CD44 was an ERK-dependent downstream effector of serglycin signaling, and serglycin activated the MAPK/β-catenin axis to induce CD44 receptor expression in a positive feedback loop. Taken together, our novel findings suggest that ECM serglycin upregulated CD44 receptor expression to maintain NPC stemness by interacting with CD44 and activating the MAPK/β-catenin pathway, resulting in NPC cell chemoresistance. These findings suggest that the intervention of serglycin/CD44 axis and downstream signaling pathway is a rational strategy for targeting NPC cancer stem cell therapy.
Department of Pharmacy, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Qiaoqiao
Q
Chu
Department of Pharmacy, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Hongbing
H
Huang
Department of Nuclear Medicine, The Second People's Hospital of Shenzhen, Shenzhen, China.
Tiejun
T
Huang
Department of Pharmacy, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Li
L
Cao
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Lixia
L
Peng
Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Simei
S
Shi
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Lisheng
L
Zheng
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Liang
L
Xu
Department of Traditional Chinese Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Shijun
S
Zhang
Department of Pathology, Saint Barnabas Medical Center, Livingston, NJ, USA.
Jialing
J
Huang
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Xinjian
X
Li
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.|Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Chaonan
C
Qian
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Bijun
B
Huang
D000818:Animals; D019898:Autocrine Communication; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism*; D025461:Feedback, Physiological; D055785:Gene Knockdown Techniques; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008954:Models, Biological; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology*; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D011509:Proteoglycans / Q000378:metabolism*; D015854:Up-Regulation; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D011509:Proteoglycans; D033921:Vesicular Transport Proteins; D051176:beta Catenin; C075430:serglycin; D048049:Extracellular Signal-Regulated MAP Kinases