RAB37 Hypermethylation Regulates Metastasis and Resistance to Docetaxel-Based Induction Chemotherapy in Nasopharyngeal Carcinoma

Abstract

Epigenetic alterations play important roles in metastasis and drug resistance through gene regulation. However, the functional features and molecular mechanisms of epigenetic changes remain largely unclear in nasopharyngeal carcinoma (NPC) metastasis. Gene regulatory network analysis was used to identify metastatic-specific dysregulated genes between normal and NPC tissues and the expression was validated in published Gene-Expression Omnibus data set. The regulatory and functional role of downregulation was examined in NPC and was validated and , and downstream target of was explored. The clinical value of methylation was evaluated in NPC metastasis and chemosensitivity. We identified as a specific hypermethylated gene that is most commonly downregulated in NPC. Moreover, downregulation was attributed to hypermethylation of its promoter and was significantly associated with metastasis- and docetaxel chemoresistance-related features in NPC. Ectopic overexpression suppressed NPC cell metastasis and enhanced chemosensitivity to docetaxel. Mechanistically, RAB37 colocalized with TIMP2, regulated TIMP2 secretion, inhibited downstream MMP2 activity, and consequently altered NPC cell metastasis. Furthermore, hypermethylation was correlated with poor clinical outcomes in patients with NPC. We developed a prognostic model based on methylation and N stage that effectively predicted an increased risk of distant metastasis and a favorable response to docetaxel-containing induction chemotherapy (IC) in NPC patients. This study shows that hypermethylation is involved in NPC metastasis and chemoresistance, and that our prognostic model can identify patients who are at a high risk of distant metastasis and might benefit from for docetaxel IC.

Hypermethylation of UCHL1 Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing Degradation of Cortactin (CTTN)

“…Methylation modification plays an important role in NPC metastasis, but the mechanisms remain poorly understood. We have previously reported that hypermethylation of the HOPX, RAB37, and SHISA3 genes might serve as molecular biomarkers to predict NPC metastasis [17,26,27]. Therefore, the mechanisms and significance of methylation regulation in NPC are worthy to be study in greater detail.…”

“…Six NPC cell lines (CNE2, SUNE1, HONE1, HNE1, 5-8F, and 6-10B) were cultured in RPMI-1640 (Invitrogen, Carlsbad, CA, USA) supplemented with 10% FBS (ExCell Bio, Shanghai, China), and two normal nasopharyngeal epithelial cell lines (NP69 and N2-Tert) were grown in KSFM (Invitrogen) supplemented with bovine pituitary extract (BD Biosciences, Franklin Lake, NJ, USA). NP69, N2-Tert and all NPC cell lines had been authenticated and were gifts from Dr. Mu-sheng Zeng (Sun Yat-sen University Cancer Center, China) [17,18]. HEK293T cells were grown in DMEM supplemented with 10% FBS, and were obtained from ATCC.…”

Expression Changes and Impact of the Extracellular Matrix on Etoposide Resistant Human Retinoblastoma Cell Lines

“…On the other hand, TIMPs inhibited tumor invasion and metastasis [101]. TIMP-2 upregulation was linked to metastasis via MMP-2 inactivation in nasopharyngeal carcinoma [102]. Additionally, a high ratio of MMP-9 to TIMP-2, implicating that a higher TIMP-2 level leads to drug resistance, was beneficial for the treatment of metastatic renal cell carcinoma [103].…”

Study on the Drug Targets and Molecular Mechanisms of Rhizoma Curcumae in the Treatment of Nasopharyngeal Carcinoma Based on Network Pharmacology

“…MMP2 is mediated by NF-κB [28], and MMP2/9 is involved in the ERK1/2-MMP2/9 extracellular signalregulated kinase signalling pathway [29]. Tissue inhibitor of metalloproteinase-2 (TIMP2) is an upstream gene of MMP2 [30], and the imbalance of MMP2/TIMP2 may have prognostic value for nasopharyngeal carcinoma. e results of immunohistochemistry analysis showed that the proportion of cells stained positive for TIMP2 in NPC was significantly higher than that in inflammatory tissues, and the proportion of positive cells increased significantly with lymph node metastasis.…”