N6-methyladenosine (m6A) modification has been convincingly identified to be a critical regulator in human cancer. However, the contribution of m6A to NSCLC gefitinib resistance is still largely unknown. Here, we screened and identified that m6A methyltransferase KIAA1429 was highly expressed in gefitinib-resistant NSCLC cells (PC9-GR), tissues, and closely related to unfavorable survival. Functionally, KIAA1429 accelerated the gefitinib resistance of NSCLC in vitro. Depletion of KIAA1429 repressed the tumor growth of PC9-GR cells in vivo. Mechanistically, KIAA1429 enhanced the mRNA stability of HOXA1 through targeting its 3′-untranslated regions (3′-UTR). Overall, our findings indicate that KIAA1429 plays essential oncogenic roles in NSCLC gefitinib resistance, which may provide a feasible therapeutic target for NSCLC.

BackgroundNon-small-cell lung cancer (NSCLC) is the major leading cause of cancer-related death around the world. The resistance to chemotherapy limits the effects of clinical treatment. The aim of this study was to identify novel mechanisms involved in NSCLC chemoresistance.Materials and methodsWe explored the public database and commercial tissue microarray to evaluate the expression of G protein-coupled receptor 35 (GPR35). We established the chemoresistant A549 cell line to further investigate the biological function of GPR35 in vitro and in vivo. Then, we measured the altered signalings that GPR35 knocking down by Western blot assay.ResultsWe demonstrated that GPR35 expression was significantly elevated in NSCLC tissues and correlated with poor prognosis. GPR35 was upregulated in our in vitro chemoresistance cell model. GPR35 depletion reduced the half maximal inhibitory concentration of chemodrugs and restored the sensitivity both in vitro and in vivo. Mechanically, we found that GPR35-mediated chemoresistance occurred partially via β-arrestin-2/Akt signaling. Furthermore, inhibition of β-arrestin-2 or Akt activation could suppress the GPR35 expression and overcome chemoresistance.ConclusionOur results suggested that GPR35 might serve as a novel therapeutic target to enhance the chemotherapy efficacy in NSCLC.

Abstract. Decreased expression of human chemokine-like factor-like MARVEL transmembrane domain-containing 3 (CMTM3) has been identified in a number of human tumors and tumor cell lines, including gastric and testicular cancer, and PC3, CAL27 and Tca-83 cell lines. However, the association between CMTM3 expression and the clinicopathological features and prognosis of esophageal squamous cell carcinoma (ESCC) patients remains unclear. The aim of the present study was to investigate the correlation between CMTM3 expression and clinicopathological parameters and prognosis in ESCC. CMTM3 mRNA and protein expression was analyzed in ESCC and paired non-tumor tissues by quantitative real-time polymerase chain reaction, western blotting and immunohistochemical analysis. The Kaplan-Meier method was used to plot survival curves and the Cox proportional hazards regression model was also used for univariate and multivariate survival analysis. The results revealed that CMTM3 mRNA and protein expression levels were lower in 82.5% (30/40) and 75% (30/40) of ESCC tissues, respectively, when compared with matched non-tumor tissues. Statistical analysis demonstrated that CMTM3 expression was significantly correlated with lymph node metastasis (P=0.002) and clinical stage (P<0.001) in ESCC tissues. Furthermore, the survival time of ESCC patients exhibiting low CMTM3 expression was significantly shorter than that of ESCC patients exhibiting high CMTM3 expression (P=0.01). In addition, Kaplan-Meier survival analysis revealed that the overall survival time of patients exhibiting low CMTM3 expression was significantly decreased compared with patients exhibiting high CMTM3 expression (P=0.010). Cox multivariate analysis indicated that CMTM3 protein expression was an independent prognostic predictor for ESCC after resection. This study indicated that CMTM3 expression is significantly decreased in ESCC tissues and CMTM3 protein expression in resected tumors may present an effective prognostic biomarker.