5-FU is an antimetabolite drug that has been widely applied for the treatment of different types of cancer in clinic, including GC (90). 5-FU is converted intracellularly to several active metabolites, including fluorodeoxyuridine monophosphate, fluorodeoxyuridine triphosphate, and fluorouridine triphosphate (91). These active metabolites can interfere in DNA replication by inhibiting thymidylate synthase (TS) activity and can also induce cytotoxicity by misincorporating its metabolites into RNA and DNA (92). However, its clinical application is still limited due to the resistance development of GC patients to this drug. Multiple lncRNAs have been found to be involved in GC resistance to 5-FU. Several oncogenic lncRNAs, such as metastasis associated in colon cancer 1-antisense 1 (MACC1-AS1), Plasmacytoma variant translocation 1 (PVT1), and HOXD antisense growth-associated long noncoding RNA (HAGLR), can promote the 5-FU resistance of GC cells. For instance, the upregulation of MACC1-AS1, induced by transforming growth factor β1 (TGF-β1), was shown to facilitate the fatty acid oxidation (FAO)-dependent resistance of GC cells to 5-FU by sponging miR-145-5p (93). In another study, Hu et al. revealed that HAGLR was upregulated in both GC tissues and cell lines. The overexpression of HAGLR significantly promoted the 5-FU resistance of GC cells by increasing the lactate dehydrogenase-A (LDHA) expression via sponging miR-338-3p. Consistent with this, the silencing of HAGLR sensitized GC cells to 5-FU (29). In addition, Du et al. showed that PVT1 promoted the drug resistance of GC cells to 5-FU through the activation of B-cell lymphoma-2 (Bcl-2) (28).

In contrast, several tumor suppressor lncRNAs can reverse 5-FU resistance in GC. For instance, Zhang et al. found that lncRNA colorectal neoplasia differentially expressed (CRNDE) was downregulated in 5-FU-resistant GC cells. The overexpression of CRNDE significantly enhanced the chemosensitivity of GC cells to 5-FU by increasing the expression of the long isoform of PICALM (encoding PICALML) by directly targeting serine/arginine-rich splicing factor 6 (SRSF6) (19). Furthermore, Han et al. revealed that lncRNA lower expression in gastric cancer (LEIGC) expressed at low levels in GC tissues. The overexpression of LEIGC significantly promoted the sensitivity of GC cells to 5-FU by inhibiting the epithelial-to-mesenchymal transition (EMT) process, whereas the knockdown of LEIGC showed the opposite effect (38).

Platinum drugs, such as cisplatin (CDDP), oxaliplatin (OXA), and carboplatin, are widely used in the treatment of human cancers, including GC (94). These drugs represent a class of cell cycle non-specific chemotherapeutic agents that can directly insert platinum into DNA to generate monoaddutcts and DNA crosslinks, which block the unwinding of DNA double helix and inhibit DNA replication, finally leading to the necrosis or apoptosis of tumor cells (3). Moreover, the monoaddutcts formed by platinum drugs and DNA also can interact with several effector proteins to produce a series of abnormal signaling factors, thereby inducing cell death (95). However, the clinical success of platinum drugs is limited due to their severe, dose-limiting side effects and resistance to treatment. Multiple lncRNAs have been reported to be involved in the GC resistance to platinum drugs (3, 96)

Several oncogenic lncRNAs can promote the resistance of GC cells to platinum drugs. For instance, Pei et al. showed that lncRNA small nucleolar RNA host gene 7 (SNHG7) was upregulated in GC tissues and CDDP-resistant cells. The silencing of SNHG7 significantly enhanced the sensitivity of the CDDP-resistant cells. Mechanistically, SNHG7 conferred to resistance of GC cells to CDDP by downregulating the expression of LDHA via sponging miR-34a (49). In another study, Li et al. revealed that lncRNA prostate cancer-associated transcript 1 (PCAT-1) was highly expressed in CDDP-resistant GC tissues and cell lines. Similarly, PCAT-1 knockdown also enhanced the sensitivity of chemoresistant GC cells to CDDP. Mechanistically, PCAT-1 epigenetically silenced phosphatase and tensin homolog deleted on chromosome 10 (PTEN) by upregulating trimethylation of histone H3 lysine 27 (H3K27me3) via targeting enhancer of zeste homolog 2 (EZH2). Consistent with this, the knockdown of PTEN counteracted the PCAT-1 silencing-induced enhancement in the CDDP sensitivity of the chemoresistant GC cells (41). In addition, Luo et al. found that lncRNA EIF3J-DT was overexpressed in OXA-resistant GC tissues and cell lines. EIF3J-DT promoted the drug resistance of GC cells to OXA by increasing autophagy-related gene 14 (ATG14) expression via sponging miR188-3p (32).

In contrast, a number of tumor suppressor lncRNAs can reverse the platinum drugs resistance. For instance, lncRNA a disintegrin-like and metalloprotease with thrombospondin type I motif 9 antisense RNA 2 (ADAMTS9-AS2) was found to be downregulated in GC tissues and cell lines. Specifically, the overexpression of ADAMTS9-AS2 enhanced the sensitivity of chemoresistant GC cells to CDDP by increasing the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) expression via sponging miR-223-3p (39). Another study revealed that the expression lncRNA cisplatin resistance-associated lncRNA (CRAL) was decreased in CDDP-resistant GC cells. The overexpression of CRAL promoted the enhancement of CDDP sensitivity of GC cells by upregulating the expression of cylindromatosis (CYLD) via sponging miR-505 (69). Additionally, in another study, lncRNA cancer susceptibility candidate 2 (CASC2) overexpression enhanced the CDDP sensitivity of GC cells by sponging miR-19a, whereas CASC2 knockdown reversed the response of GC cells to CDDP. Consistent with this, miR-19a overexpression counteracted the CASC2 overexpression-induced enhancement in the CDDP sensitivity of GC cel (70).

ADR, also known as doxorubicin (DOX), is one of the most commonly prescribed and time-tested chemotherapeutic drugs (97). It can produce free radical to induce the impairment of DNA and the cell membrane, thereby resulting in tumor cell death. Moreover, ADR suppresses the biosynthesis of macromolecules by interacting with DNA via intercalation, thereby inhibiting DNA topoisomerase II, and leading to the stagnation of DNA replication (98). Several oncogenic lncRNAs, such as lncR-D63785, urothelial cancer-associated 1 (UCA1), and nuclear paraspeckle assembly transcript 1 (NEAT1), have been reported to promote ADR resistance in GC (81, 83, 84). For instance, in our previous work, we found that lncR-D63785 was highly expressed in both GC tissues and cell lines. The overexpression of lncR-D63785 conferred the ADR resistance of GC cells by increasing myocyte enhancer factor 2D (MEF2D) expression via sponging miR-422 (84). In another study, Shang showed that UCA1 was significantly upregulated in GC tissues and cells. The silencing of UCA1 could reverse the ADR resistance of GC cells and promote apoptosis induced by ADR by increasing cleaved Poly(ADP-ribose) polymerase (PARP) expression and decreasing Bcl-2 expression (81). Similarly, Zhang et al. showed that NEAT1 knockdown in ADR-resistant GC cells could enhance the sensitivity of GC cells to ADR and promote apoptosis induced by AD (83). In addition, another two lncRNAs, regulator of reprogramming (ROR) and MDR-related and upregulated lncRNA (MURL), were also found to promote ADR resistance in GC cells via regulating the expression of various genes (85, 99).

PTX is a tricyclic diterpenoid compound produced from Taxus brevifolia and is considered to be one of the most successful natural chemotherapeutic agents available (100). As an antimitotic agent, PTX facilitates the assembly of tubulin into microtubules and the lengthening of the tubulin polymer, leading to the inhibition of microtubule depolymerization. The enhancement of microtubule stability interferes with microtubules’ polymerization dynamics, leading to G2/M cell cycle arrest of tumor cells (101, 102). Several oncogenic lncRNAs have been shown to be responsible for the development of PTX resistance in GC. For instance, Shang et al. found that lncRNA cancer susceptibility candidate 9 (CASC9) was significantly upregulated in both GC tissues and cells. The silencing of CASC9 in drug-resistant GC cells restored the sensitivity of cells to PTX via downregulating the expression of multidrug resistance protein 1 (MDR1) (79). Moreover, An et al. revealed that lncRNA ZNFX1 antisense RNA 1 (ZFAS1) was highly expressed in GC tissues. The knockdown of ZFAS1 enhanced the sensitivity of GC cells to PTX by decreasing β-catenin expression. Consistent with this, the overexpression of β-catenin reversed the ZFAS1 knockdown-induced resistance of GC cells to PTX (87). Wang et al. showed that lncRNA HOX transcript antisense RNA (HOTAIR) was upregulated in GC tissues. The overexpression of HOTAIR enhanced the PTX and ADR resistance in GC cells by upregulating glypican-5 (GPC5) and protein tyrosine phosphatase non-receptor type 14 (PTPN14) expression via sponging miR-217 (88). In another study, Hu et al. demonstrated that the expression of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was upregulated in PTX-resistant GC cells and that the silencing of MALAT1 enhanced the sensitivity of GC cells to PTX. Mechanistically, MALAT1 acted as a ceRNA to decrease ATG12 expression by sponging miR-23b-3p, leading to the enhancement of PTX resistance in GC cells (103).

VCR is a vinca alkaloid that is often used in combination with other chemotherapeutic agents to treat a variety of cancers, including GC (104). Similar with PTX, VCR is also an antimitotic agent that blocks tubulin polymerization and disables spindle formation. This inhibition causes the mitosis of tumor cells to arrest at metaphase, particularly during the M and S phases (105). In addition, VCR also can interfere with the synthesis of nucleic acids and proteins by blocking glutamic acid utilization (106). Several lncRNAs have been reported to be involved in the resistance of GC cells to VCR. For instance, the high expression of oncogenic lncRNA ROR was associated with the increased MDR of GC patients. The silencing of ROR promoted the apoptosis of drug-resistant GC cells in response to VCR and ADR treatment by decreasing multidrug resistance-associated protein 1 (MRP1) expression (78). In Wang et al.’s study, lncRNA MRUL was found to be upregulated in the VCR-resistant GC cells. The knockdown of MRUL promoted apoptosis and decreased VCR release in the VCR-resistant GC cells by upregulating MRP1 expression (85).

An increasing number of studies have shown that lncRNAs regulate GC drug resistance by targeting cancer-related signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)/AKT, Wnt/β−catenin, and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) signaling pathways (46, 53, 107, 108) (Figure 2). These lncRNAs can change the sensitivity of GC cells to chemotherapy drugs by altering the activity or expression of some key components in these signaling pathways.

The PI3K/AKT signaling pathway is a carcinogenic pathway involved in a variety of physiological processes, including proliferation, apoptosis, differentiation, migration, and invasion (109). The aberrant activation of this pathway is closely associated with many aspects of cancer progression, including drug resistance (110, 111). Several lncRNAs have been found to be involved in GC drug resistance by modulating the activity of the PI3K/AKT signaling pathway. For instance, Dai et al. revealed that lncRNA MALAT1 was highly expressed in GC tissues and that its upregulation enhanced the resistance of GC cells to CDDP. Consistent with this, the knockdown of MALAT1 reduced the inhibition of MALAT1 on the apoptosis of the CDDP-resistant GC cells. Mechanistically, MALAT1 activated the PI3K/AKT signaling pathway by upregulating the level of phosphorylated PI3K (p-PI3K) and p-AKT, leading to the enhancement of the CDDP resistance of GC cells (40). Zeng et al. found that lncRNA XLOC_006753 promoted the resistance of GC cells to 5-FU and CDDP by activating the PI3K/AKT signaling pathway. The silencing of XLOC_006753 in MDR GC cells significantly decreased the levels of PI3K, p-AKT, and phosphorylated mechanistic target of rapamycin (p-mTOR) (36). Moreover, Wu et al. demonstrated that the high expression of lncRNA Forkhead Box D1-antisense 1 (FOXD1‐AS1) increased the resistance of GC cells to CDDP by activating the PI3K/AKT signaling pathway via the upregulation of PIK3CA (60). PTEN is a well-known negative regulator of the PI3K/AKT signaling pathway (112, 113). Li et al. showed that PCAT-1 could downregulate PTEN expression by targeting EZH2 in CDDP-resistant GC cells, indicating that PCAT-1 might contribute to the resistance of GC cells to CDDP by activating the PI3K/AKT signaling pathway via downregulating PTEN expression (41).

The Wnt/β−catenin signaling pathway is a conserved cancer-related pathway participating in cancer progression by promoting CSC renewal, proliferation, and differentiation, thereby playing crucial roles in carcinogenesis and therapy response (114, 115). The aberrant activation of the Wnt/β−catenin pathway contributes to the development of drug resistance in a variety of cancers, including GC (116, 117). Several lncRNAs have been reported to be involved in GC drug resistance by regulating the expression of key components in the Wnt/β-catenin signaling pathway. For instance, Xu et al. showed that lncRNA ZFAS1 was highly expressed in GC tissues. The knockdown of ZFAS1 enhanced the sensitivity of GC cells to PTX and cis-platinum by inactivating the Wnt/β-catenin signaling pathway via downregulating β-catenin and phosphorylated glycogen synthase kinase-3β (p-GSK3β) level and increasing naked cuticle homolog 2 (NKD2) expression. Consistent with this, the overexpression of β-catenin reversed the inhibition of the GC drug resistance induced by the ZFAS1 knockdown (87). In another study, Cheng et al. revealed that lncRNA HOTAIR was upregulated in both GC tissues and cell lines. The knockdown of HOTAIR reduced the resistance of GC cells to CDDP. Mechanistically, HOTAIR activated the Wnt/β-catenin signaling pathway by upregulating the level of Wnt1 and β-catenin via sponging miR-34a in GC cells, resulting in the enhancement of CDDP resistance (107). In addition, some lncRNAs, such as small nucleolar RNA hostgene 11 (SNHG11), HOXC cluster antisense RNA 1 (HOXC-AS1), and DLGAP1 antisense RNA 2 (DLGAP1-AS2), have also been found to regulate the expression of the key components in the Wnt/β-catenin signaling pathway during GC progression (20, 118–120), indicating that they may also influence the development of drug resistance in GC by targeting the Wnt/β-catenin pathway.

The MAPK/ERK signaling pathway is a classical oncogenic pathway, and its dysregulation has been shown to be closely associated with the development of drug resistance in GC (121, 122). Particularly, Miao et al. found that the overexpression of lncRNA BRAF-activated non-coding RNA (BANCR) enhanced the resistance of GC cells to CDDP by activating the MAPK/ERK signaling pathway via upregulating the level of p-ERK1/2. Consistent with this, Ly3214996 (an ERK inhibitor) treatment reversed the BANCR overexpression-induced CDDP resistance of GC cells by decreasing the p-ERK1/2 level (53). In addition, lncRNAs can also regulate GC drug resistance by targeting the nuclear factor-kappaB (NF-κB) signaling pathway. Fu et al. revealed that lncRNA ASB16 antisense RNA 1 (ASB16-AS1) promoted the CDDP resistance of GC cells by activating the NF-κB signaling pathway. Mechanistically, the overexpression of ASB16-AS1 upregulated the level of NF-κB pathway-related proteins (p-IKK, p-IκB and Nuclear p65) by increasing tripartite motif-containing 37 (TRIM37) expression via sponging miR-3918 and miR4676-3p, leading to the enhancement of CDDP resistance in GC (63). Collectively, these findings suggest that targeting the oncogenic signaling pathways is a common mechanism for lncRNAs in the development of GC drug resistance. Thus, in-depth studies on the underlying mechanisms of lncRNAs in the regulation of the GC signaling pathway may provide novel insights into the development of therapeutic strategies against GC drug resistance.

An important function of most chemotherapeutic drugs is to promote the effective elimination of cancer cells by inducing apoptosis (123, 124). Therefore, the dysregulation of apoptosis is one of the main factors resulting in the occurrence of drug resistance. An increasing amount of evidence has shown that lncRNAs participate in the development of GC drug resistance by regulating apoptotic proteins or related pathways (65, 74, 125).

Bcl-2 family proteins are key regulators of the mitochondrial apoptotic pathway and are divided into two major groups: anti-apoptotic (e.g., Bcl-2, Mcl-1, and Bcl-xl) and pro-apoptotic (e.g., Bax, Bim, and Bak) (126, 127). Li et al. showed that lncRNA small nucleolar RNA hostgene 5 (SNHG5) was upregulated in CDDP-resistant GC tissues and cell lines. Specifically, SNHG5 overexpression in GC cells reduced the CDDP cytotoxicity and promoted cell apoptosis by upregulating Bax and downregulating Bcl-2 level. Consistent with this, the silencing of SNHG5 promoted the apoptosis of the CDDP-resistant GC cells (45). Qiao et al. revealed that lncRNA HMGA1P4 overexpression inhibited apoptosis of the CDDP-resistant GC cells by decreasing Bcl-2 and caspase3 expression and increasing Bax expression (37). Moreover, Fang et al. found that lncRNA UCA1 was highly expressed in GC tissues. The overexpression of UCA1 increased the MDR of GC cells to ADR, DDP, and 5-FU and decreased the cell apoptosis induced by ADR by upregulating Bcl-2 and downregulating caspase3 via sponging miR-27b. Consistent with this, UCA1 knockdown decreased the MDR of GC cells, and increased the ADR-induced cell apoptosis (31). Zhang et al. demonstrated that lncRNA gastric carcinoma high expressed transcript 1 (GHET1) overexpression significantly enhanced the resistance of GC cells to CDDP and inhibited cell apoptosis by downregulating Bax level and upregulating Bcl-2, MDR1 and MRP1 level. Conversely, the knockdown of GHET1 decreased MDR and promoted apoptosis in CDDP-resistant GC cells (61). Moreover, Zong et al. found that lncRNA LINC00162 overexpression increased the sensitivity of GC cells to 5-aza-2’-deoxycytidine and cell apoptosis by interacting with heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) and downregulating Bcl-XL level (128).

In addition, Cheng et al. showed that the overexpression of UCA1 could inhibit the apoptosis induced by CDDP in GC cells by upregulating cytochrome P450 1B1 enzyme (CYP1B1) expression via sponging miR-513a-3p, which lead to the enhancement of the CDDP resistance of GC cells (129). In another study, the overexpression of lncRNA differentiation antagonizing non-protein coding RNA (DANCR) was found to increase survival and decrease apoptosis in CDDP-resistant GC cells by upregulating the expression of MDR1 and MRP1 (52). Moreover, Wang et al. revealed that lncRNA CRAL overexpression promoted CDDP-induced apoptosis in GC cells by upregulating CYLD expression via sponging miR-505 (69). Zhang et al. demonstrated that lncRNA FAM84B-AS promoted the resistance of GC cells to platinum drugs by inhibiting the apoptotic pathways. Mechanistically, FAM84B-AS knockdown significantly increased the level of Bax, caspase3, caspase7, and caspase9 and then decreased the level of Bcl-2 and Bcl-xl by upregulating FAM84B expression to further inhibit the GC cell apoptosis (58). Taken together, these findings demonstrate that lncRNAs can act as oncogenes to contribute to drug resistance by suppressing cell apoptosis in GC, at least partially due to their modulation on the expression of apoptotic proteins. However, the exact mechanisms are still not fully elucidated. Therefore, in-depth studies are required to further understand the detailed mechanism of lncRNAs in GC drug resistance, which may provide new insights for the development of lncRNA-based therapeutics strategies for patients against drug resistance.

Excessive drug efflux mediated by multiple cell membrane transporter proteins, such as ATP-binding cassette (ABC) proteins, is one of the main mechanisms of drug resistance in cancer cells (130). It has been reported that the overexpression of ABC proteins could enhance the efflux of anticancer drugs from cancer cells, thereby reducing their efficacy and leading to the resistance of cancer cells to these anticancer drugs (131). Currently, at least three members of ABC family have been shown to be closely associated with MDR, particularly MDR1 (also known as ABCB1 and P-glycoprotein), MRP (also known as ABCC1), and breast cancer resistant protein (BCRP) (also known as ABCG2) (132).

An accumulating number of studies have shown that lncRNAs participate in the regulation of excessive drug efflux in GC cells by targeting ABC proteins (Figure 3). MDR1 was the first-identified ABC protein associated with MDR (133). Several lncRNAs, such as bladder cancer-associated transcript 1 (BLACAT1), MRUL, PVT1, and CASC9, have been reported to regulate the development of MDR in GC by directly or indirectly targeting MDR1. For instance, Xu et al. found that lncRNA BLACAT1 was upregulated in OXA-resistant GC tissues and cell lines and that its overexpression promoted the OXA resistance of these GC cells by upregulating MDR1 expression via sequestering miR-361 (72). Wang et al. revealed that lncRNA MRUL was highly expressed in MDR GC cells with the knockdown of MRUL enhancing the sensitivity of these cells to ADR and VCR by downregulating MDR1 expression (85). Shang et al. showed that lncRNA CASC9 knockdown restored the sensitivity of MDR GC cells to PTX and ADR by decreasing MDR1 expression (79). In addition, Zhang et al. demonstrated that the upregulation of lncRNA GHET1 facilitated the development of MDR in GC cells by upregulating MDR1, Bcl-2, and MRP1 level and downregulating Bax level (61). Taken together, these findings indicate that lncRNAs can participate in the regulation of drug resistance in GC cells by altering the drug efflux. Further investigations on the underlying mechanisms of lncRNAs in drug efflux regulation is of great importance in helping GC patients overcome drug resistance.

EMT is a process by which epithelial cells lose their junctions and polarity, and gain migratory and invasive characteristics, producing a fibroblast-like phenotype (134, 135). The aberrant activation of the EMT process is closely associated with GC drug resistance (136). An increasing amount of evidence has shown that lncRNAs are involved in GC drug resistance by modulating the EMT process. For instance, Mao et al. revealed that lncRNA HOXA transcript at the distal tip (HOTTIP) was upregulated in CDDP-resistant GC cells. The knockdown of HOTTIP promoted the EMT progress by upregulating the level of the epithelial markers (E-cadherin and ZO-1) and downregulating the level of the mesenchymal markers (N-cadherin, vimentin, ZEB-1, and Twist), leading to the enhancement of MDR in GC cells (42). In another study, Han et al. found that lncRNA LEIGC was downregulated in GC tissues with its overexpression enhancing the sensitivity of GC cells to 5-FU by suppressing the EMT process (38). Moreover, Jia et al. demonstrated that lncRNA HOTAIR was highly expressed in GC tissues. The overexpression of HOTAIR significantly promoted the EMT process by increasing the level of N‐cadherin and vimentin and decreasing E‐cadherin level in GC cells that were subject to treatment via chemo‐therapies (80). In addition, some lncRNAs, such as metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1), microvascular invasion in hepatocellular carcinoma (MVIH), NEAT1, and gastric cancer associated transcript 3 (GACAT3), have also been found to modulate the expression of EMT markers during GC progression (16, 137–140), indicating that these lncRNAs may also be involved in the development of drug resistance in GC by regulating the EMT process. EMT is a core link of metastatic process, which is closely associated with cancer recurrence and drug resistance. Therefore, dysregulated lncRNAs are likely to play a positive role in the development of GC drug resistance by aberrantly activating the EMT process. These findings support the hypothesis that lncRNAs are key regulators in GC drug resistance, but the molecular mechanisms still need further investigation.

CSCs are a unique subpopulation of cancer cells within a tumor with high tumorigenic potency and have been recognized as the main cause of the chemotherapeutic resistance, metastasis, and recurrence of cancer (141, 142). An accumulating number of studies have shown that lncRNAs can participate in the regulation of GC drug resistance by regulating the characteristics of CSC. For instance, Sun et al. showed that lncRNA small nucleolar RNA hostgene 3 (SNHG3) upregulation was positively associated with the CDDP resistance and stemness of GC cells, whereas SNHG3 downregulation inhibited the stem cell-like properties of these GC cells. Mechanistically, SNHG3 significantly enhanced the stemness of GC cells by increasing ADP-ribosylation factor-like protein 2 (ARL2) expression via sponging miR-3619-5p, leading to the enhancement of GC CDDP resistance (66). Fu et al. revealed that lncRNA ASB16 antisense RNA 1 (ASB16-AS1) was highly expressed in GC tissues. Specifically, the overexpression of ASB16-AS1 strengthened the stem cell-like features of GC cells by upregulating TRIM37 expression via sponging miR-3918 and miR-4676-3p, resulting in the enhancement of CDDP resistance in GC (63). Wang et al. found that lncRNA ROR was highly expressed in CD133+ gastric CSCs (GCSCs). The overexpression of ROR promoted the pluripotent state of GCSCs by upregulating several key stemness transcriptional factors, such as octamer-binding transcription factor 4 (OCT4), SRY-box transcription factor 2 (SOX2), and NANOG (143). Furthermore, lncRNAs MALAT1 and testis-associated highly-conserved oncogenic long non-coding RNA (THOR) have been shown to increase the stemness of GC cells by enhancing SOX2 and SOX9 mRNA stability, respectively (144–146). In addition, the upregulation of lncRNAs histocompatibility leukocyte antigen complex P5 (HCP5) and MACC1-AS1 induced via mesenchymal stem cell (MSC) co-culturing was found to enhance the stemness and drug-resistance of GC cells by droving FAO (93, 147).

Autophagy is a complex, highly conserved self-metabolic process that is essential for maintaining cellular homeostasis during stress conditions, such as hypoxia and nutrient deprivation (148, 149). It has been reported that autophagy plays dual roles in GC drug resistance. On the one hand, it can promote drug resistance by protecting GC cells from the cytotoxicity of chemotherapeutic agents. On the other hand, it can reverse drug resistance through facilitating apoptosis and/or inhibiting EMT (150). Therefore, targeting autophagy may be one of the crucial therapeutic strategies against GC drug resistance. Furthermore, an increasing number of studies have shown that lncRNAs are involved in GC drug resistance by targeting autophagy (68, 103) (Figure 4).

Zhang et al. showed that the expression of lncRNA CRNDE was downregulated in CDDP-resistant GC cells. The low level of CRNDE promoted the MDR of GC cells to 5-FU and OXA by upregulating autophagy flux in GC. Mechanistically, CRNDE reduced the alternative splicing of PICALM by decreasing the protein stability of SRSF6, leading to the enhancement of autophagy-mediated drug resistance (19). In another study, Wang et al. found that lncRNA non-coding RNA activated by DNA damage (NORAD) was highly expressed in OXA-resistant GC tissues, with its upregulation in the OXA-resistant GC cells promoting the autophagy flux by stabilizing the autophagy related gene 5 (ATG5)-ATG12 complex via sponging miR-433-3p, leading to the enhancement of CDDP resistance (76). Moreover, Luo et al. revealed that lncRNA EIF3J-DT was upregulated in drug-resistant GC cells. The high expression of EIF3J-DT activated autophagy and induced drug resistance in these GC cells by upregulating ATG14 expression via sequestering miR188-3p (32). In addition, some lncRNAs, such as FEZF1 antisense RNA 1 (FEZF1-AS1), LINC00641, and MALAT1, have also been found to mediate drug resistance in GC by activating autophagy (33, 75, 103). Collectively, these findings suggest that the lncRNA regulation of autophagy is an important mechanism in the development of GC drug resistance. However, how lncRNAs participate in GC drug resistance by modulating autophagy is still not fully understood. Accordingly, in-depth studies are required to elucidate its exact mechanisms.

The recurrence and mortality rates of GC are still high due to the lack of efficient approaches for its early diagnosis and prognostic assessment in clinical practice. Currently, some conventional biomarkers, such as carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4), have been used in clinic, but the low diagnostic accuracies of these biomarkers limit their further application (151, 152). Thus, the screening and identification of valuable molecular biomarkers with high specificity and sensitivity is very essential for GC patients, particularly those with a poor response to chemotherapy, to obtain timely and effective treatment.

In recent years, a large number of studies have shown the key role of drug resistance-related lncRNAs in the pathogenesis of GC. Additionally, the differential expression of these lncRNAs endows them with great potential as biomarkers for the diagnosis, prognosis and treatment of GC patients (Table 2). For instance, the expression of lncRNA SNHG5 was significantly downregulated in the serum and tissues of GC patients before operation as well as those with poor prognosis, and its downregulation was closely associated with drinking history and Tumor-Node-Metastasis (TNM) stages in these patients, indicating that SNHG5 is a survival predictor of short-term adverse events in GC patients (155). In another study, the overexpression of SNHG5 decreased CDDP cytotoxicity and inhibited apoptosis in GC cells (45). This data suggests that SNHG5 processes a high diagnostic value in prognosis prediction and is a promising biomarker for the early diagnosis of GC. In another study, lncRNA PVT1 was upregulated in both the tissues and cells of CDDP‐resistant patients. This overexpression of PVT1 promoted the apoptosis induced by CDDP in GC cells by upregulating the expression of MDR‐related genes, such as MDR1, mTOR, and MRP (156). Furthermore, the upregulation of PVT1 was closely associated with late tumor stage (III–IV), lymph node metastasis, and OS/disease-free survival (DFS) (153). These findings provide evidence that PVT1 can be used as a candidate biomarker for the diagnosis and personalized therapeutic treatment of GC patients. Besides, lncRNA NORAD was found to be highly expressed in OXA-resistant GC tissues. The overexpression of NORAD enhanced the autophagy flux in OXA-resistant GC cells by stabilizing the ATG12 complex via sponging miR-433-3p. This data suggests that NORAD can serve as a clinically useful biomarker for predicting OXA resistance in GC. In addition, some drug resistance-related lncRNAs, such as UCA1, DDX11 antisense RNA 1 (DDX11-AS1), and XLOC_006753, have also exhibited great potential as prognostic biomarkers for GC patients (36, 73, 81). However, the potential value of lncRNAs as biomarkers for GC patients needed be further confirmed via larger population-based studies.

LncRNAs play crucial roles in practically all aspects of GC progression, including drug resistance, suggesting their great clinical value as therapeutic targets or therapeutic agents in GC patients, particularly those exhibiting a poor response to chemotherapy. Targeting these lncRNAs may provide novel insights into the development of therapeutic strategies for reversing GC drug resistance. For instance, Xu et al. showed that lncRNA DANCR was strongly upregulated in CDDP-resistant GC tissues and cell lines, and its knockdown by small interfering RNA (siRNA) was shown to decrease survival and increase apoptosis in CDDP-resistant GC cells (52). Lan et al. revealed that lncRNA antisense non-coding RNA in the INK4 locus (ANRIL) was highly expressed in CDDP and 5-FU-resistant GC tissues and cell lines. The knockdown of ANRIL by siRNA could inhibit the development of the MDR of GC cells to CDDP and 5-FU by upregulating the expression of MDR1 and MRP1 (34). Han et al. found that the high expression of lncRNA X inactive-specific transcript (XIST) contributed to the CDDP resistance of GC cells. The knockdown of XIST by siRNA significantly inhibited cell proliferation and promoted apoptosis via modulating the expression of Aurora kinase B (AURKB) (50). These evidences strongly suggest that lncRNAs possess great potential as effective therapeutic targets reversing GC drug resistance. Thus, the identification and synthesis of novel drugs targeting lncRNA is a promising pathway for the clinical treatment of GC patients, particularly those with drug resistance. Furthermore, lncRNAs can be regulate by several oncogenic signaling pathways, such as Wnt/β−catenin and STAT3 signaling pathways (157, 158), indicating that the screening and synthesis of novel inhibitors targeting the nodes of these pathways is also an attractive strategy to treat GC. In addition, several efficient RNA‐based techniques, such as siRNA, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) protein 9 (CRISPR/Cas9), epigenetic modifiers, and transcription activator-like effector nuclease, are also used to target lncRNAs in GC treatment (159). However, lncRNA-based therapies have not yet been translated into GC treatment in clinic, and further investigations are still needed to elucidate the mechanisms of lncRNAs in GC drug resistance.