CCL2 supports colorectal cancer proliferation, invasion and metastasis through activating lncRNA GSTM3TV2/ATF4 signaling

Objective: Despite extensive research and advances in biological knowledge, therapeutic strategies, and prognostic outcomes, colorectal cancer (CRC) remains a common malignancy around the world. Elucidating molecular determinants promoting CRC progression will help develop novel, available, and effective treatment modalities. In this study, we proposed a novel C-C motif chemokine 2 (CCL2)/long noncoding RNA lncRNA glutathione S-transferase mu 3, transcript variant 2 ( GSTM3TV2 )/activating transcription factor 4 (ATF4) mechanism responsible for promoting CRC progression. Methods: CRC cells were exposed to 100 ng/ml recombinant CCL2, and/or transfected with GSTM3TV2 or ATF4 siRNA or pcDNA3.1 vector with the full-length of GSTM3TV2 or ATF4 sequence. Cell proliferation, invasion and metastasis were investigated through CCK-8, wound healing, Transwell, and subcutaneous mouse xenograft models. GSTM3TV2 and ATF4 expression levels were measured via qRT-PCR and immunofluorescence. Results: CCL2 treatment upregulated lncRNA GSTM3TV2 expression and conferred proliferative, invasive and metastatic potential of CRC cells, but such effects were effectively reversed by endogenous silencing of GSTM3TV2 . ATF4 was determined to be a downstream factor of GSTM3TV2 , whose expression levels were positively modulated by GSTM3TV2 . Endogenous silencing of ATF4 reversed the impact of overexpressing GSTM3TV2 or CCL2 treatment on heightening CRC cells proliferation, invasion and metastasis, thus preventing CRC progression. Conclusion: Altogether, our findings suggest that the CCL2/lncRNA GSTM3TV2 /ATF4 signaling could be an important mechanism underlying CRC progression, offering potential theoretical basis for the clinical therapy of CRC.