Long non-coding RNAs towards precision medicine in gastric cancer: early diagnosis, treatment, and drug resistance

Abstract

Gastric cancer is a deadly disease and remains the third leading cause of cancer-related death worldwide. The 5-year overall survival rate of patients with early-stage localized gastric cancer is more than 60%, whereas that of patients with distant metastasis is less than 5%. Surgical resection is the best option for early-stage gastric cancer, while chemotherapy is mainly used in the middle and advanced stages of this disease, despite the frequently reported treatment failure due to chemotherapy resistance. Therefore, there is an unmet medical need for identifying new biomarkers for the early diagnosis and proper management of patients, to achieve the best response to treatment. Long non-coding RNAs (lncRNAs) in body fluids have attracted widespread attention as biomarkers for early screening, diagnosis, treatment, prognosis, and responses to drugs due to the high specificity and sensitivity. In the present review, we focus on the clinical potential of lncRNAs as biomarkers in liquid biopsies in the diagnosis and prognosis of gastric cancer. We also comprehensively discuss the roles of lncRNAs and their molecular mechanisms in gastric cancer chemoresistance as well as their potential as therapeutic targets for gastric cancer precision medicine.

Keywords: Cancer treatment; Chemoresistance; Early diagnosis; Gastric cancer; LncRNA; Precision medicine.

Fig. 1

LncRNAs regulate chemoresistance through apoptosis. There are two apoptosis pathways, i.e. extrinsic pathway and intrinsic pathway (mitochondrial pathway). ①-② LncRNAs act as a ceRNA, directly bind to mRNAs or proteins, and regulate multidrug resistance (MDR) through extrinsic and intrinsic pathways of apoptosis. ③-⑤ LncRNAs also regulate apoptosis-mediated MDR through PI3K/AKT, Wnt/β-catenin, Hippo, and HIF-1α signaling pathways

Fig. 2

LncRNAs regulate EMT-mediated chemoresistance. ① LncRNAs act as a ceRNA, directly bind to mRNAs or proteins, and regulate EMT-mediated multidrug resistance (MDR) by modulating PI3K/AKT and Wnt/β-catenin signaling pathways. ②-③ LncRNAs also regulate EMT-mediated MDR by targeting EMT markers or transcription factors

Fig. 3

LncRNAs regulate chemoresistance through cancer cell stemness. ①-③ LncRNAs act as a ceRNA, directly bind to mRNAs or proteins, and regulate cancer cell stemness and multidrug resistance (MDR) by modulating stemness-related markers. ④ LncRNAs also regulate cancer cell stemness and MDR through modulating Wnt/β-catenin signaling pathway

Fig. 4

LncRNAs regulate autophagy-mediated chemoresistance. The process of autophagy is divided into five distinct stages: initiation, vesicle nucleation, vesicle elongation, vesicle fusion, and cargo degradation. LncRNAs act as a ceRNA, directly bind to mRNAs or proteins, and regulate autophagy-mediated multidrug resistance (MDR) by targeting ATGs or ATG-LC3 complex

Fig. 5

LncRNAs regulate chemoresistance through modulating MDR-related genes. The ABC transporters export chemotherapy drugs out of the cells, leading to resistance with reduced concentrations of the drugs intracellularly. The transporters also sequestrate intracellular drugs into membrane vesicles in the cytoplasm, resulting in chemotherapy resistance. LncRNAs can act as a ceRNA, directly bind to mRNAs or proteins, and regulate MDR through up-regulating the expression of MDR-related genes (MDR1 and MRP1)