The function of LncRNAs and their role in the prediction, diagnosis, and prognosis of lung cancer

Abstract

Lung cancer remains a major threat to human health. Low dose CT scan (LDCT) has become the main method of early screening for lung cancer due to the low sensitivity of chest X-ray. However, LDCT not only has a high false positive rate, but also entails risks of overdiagnosis and cumulative radiation exposure. In addition, cumulative radiation by LDCT screening and subsequent follow-up can increase the risk of lung cancer. Many studies have shown that long noncoding RNAs (lncRNAs) remain stable in blood, and profiling of blood has the advantages of being noninvasive, readily accessible and inexpensive. Serum or plasma assay of lncRNAs in blood can be used as a novel detection method to assist LDCT while improving the accuracy of early lung cancer screening. LncRNAs can participate in the regulation of various biological processes. A large number of researches have reported that lncRNAs are key regulators involved in the progression of human cancers through multiple action models. Especially, some lncRNAs can affect various hallmarks of lung cancer. In addition to their diagnostic value, lncRNAs also possess promising potential in other clinical applications toward lung cancer. LncRNAs can be used as predictive markers for chemosensitivity, radiosensitivity, and sensitivity to epidermal growth factor receptor (EGFR)-targeted therapy, and as well markers of prognosis. Different lncRNAs have been implicated to regulate chemosensitivity, radiosensitivity, and sensitivity to EGFR-targeted therapy through diverse mechanisms. Although many challenges need to be addressed in the future, lncRNAs have bright prospects as an adjunct to radiographic methods in the clinical management of lung cancer.

Keywords: EGFR; LDCT; biomarker; chemosensitivity; diagnosis; lncRNA; lung cancer; predictive; prognosis; radiosensitivity.

FIGURE 1

In lung cancer, lncRNAs regulate chemosensitivity through various mechanisms. A, LncRNAs regulate chemosensitivity through different signaling pathways. P: phosphorylated.①② LncRNAs regulate EMT‐mediated chemosensitivity by MAPK/ERK signaling pathways.④⑤⑥ LncRNAs regulate cancer cell stemness, EMT and chemosensitivity by regulating Wnt/β‐catenin signaling pathway. ③⑧ LncRNAs regulate chemosensitivity by modulating PI3K/AKT/mTOR and NF‐κB signaling pathway.⑦ LncRNAs regulate chemosensitivity through modulating STAT3 signaling pathway.⑨⑩ LncRNAs also regulate chemosensitivity through crosstalk between apoptosis and autophagy. Beclin‐1 doesn't produce two fragments named “N” and “C.” Beclin‐1 is activated and can induce autophagy and inhibit apoptosis regulated by mitochondrial pathway.②⑥⑦⑨⑩ LncRNAs sponge miRNAs and then regulate downstream signaling pathways. (Note: The lncRNA‐miRNA complex is regarded as a whole, and the arrows emitted by the complex in the figure represent that the complex promotes the expression of microRNA target genes. B, LncRNAs regulate autophagy‐mediated chemosensitivity. The process of autophagy is divided into the following five different stages: ①Autophagy initiation; ②Nucleation; ③Elongation; ⑤Fusion with the lysosome; and ⑤Degradation. LncRNAs bind to miRNAs, or directly target autophagy protein Beclin‐1 or ATG family proteins or LC3 to regulate autophagy, thereby affecting chemosensitivity. C, LncRNAs regulate chemosensitivity by modulating MDR‐related genes. The ABC transporters not only excrete intracellular chemotherapy drugs, but also mediate lysosomal sequestration of chemotherapy drugs, then reducing the concentration of intracellular chemotherapy drugs, which makes lung cancer cells resistant to chemotherapy. LncRNAs bind to miRNAs or directly regulate MDR through modulating the expression of MDR‐related genes (MDR1, MRP1, and MRP7)

FIGURE 2

LncRNAs sponge microRNAs and then regulate radiosensitivity through different signaling pathways. P: phosphorylated. ①②③④⑦ LncRNAs regulate apoptosis‐mediated radiosensitivity. Specifically, ①②③⑦ lncRNAs affect radiosensitivity by regulating the intrinsic pathway of apoptosis, Hippo, and PI3K/AKT signaling pathways. ⑤ LncRNAs regulate autophagy‐mediated radiosensitivity through HIF‐1α signaling pathway. ①⑥⑦⑧ lncRNAs also regulate EMT‐mediated radiosensitivity via targeting EMT markers and matrix metalloproteinases (MMPs). (Note: The lncRNA‐miRNA complex is regarded as a whole, and the arrows emitted by the complex in the figure represent that the complex promotes the expression of miRNA target genes)

FIGURE 3

LncRNAs regulate sensitivity to EGFR‐targeted therapy through different signaling pathways in EGFR‐TKIs‐resistant lung cancer cells. P: phosphorylated. ①②③④ LncRNAs regulate sensitivity to EGFR‐targeted therapy by modulating MAPK/ERK, PI3K/AKT/mTOR, STAT3 signaling pathways, and mitochondrial pathway.②⑤ LncRNAs regulate cell cycle‐dependent sensitivity to EGFR‐targeted therapy. ①③⑥ lncRNAs also regulate EMT‐mediated sensitivity to EGFR‐targeted therapy via targeting EMT markers or transcription factors. (Note: The complex (e.g., lncRNA‐miRNA, lncRNA‐protein) is regarded as a whole, and the arrows emitted by the complex in the figure represent that the complex promotes the expression of target genes)

FIGURE 4

LncRNAs are used as a diagnostic tool for early lung cancer screening. Because LDCT has a high false positive rate, lncRNAs can be act as an auxiliary detection tool to diagnose diseases. LncRNAs are stable in the blood. After LDCT screening, patients were drawn blood to extract RNAs. Identifying the expression levels of different lncRNAs in the patient's blood by PCR, which can distinguish between lung cancer and benign lung disease

FIGURE 5

The disadvantages of CRX and LDCT and the characteristics and advantages of lncRNAs in the clinical applications of lung cancer

FIGURE 6

The lncRNAs from Tables S2, S3, S4, S5, and S6 were selected and divided into five types according to their different uses as markers: chemosensitivity, radiosensitivity, sensitivity to EGFR‐targeted therapy, diagnosis, and prognosis. They were sequentially labeled with serial numbers 1–5. A, The Venn diagram is made. Among them, the lncRNA with five types of functions is GAS5. The lncRNA with functions of 1 and 3 and 4 and 5 are HOTAIR and MALAT1. The lncRNAs with functions of 1 and 2 and 4 and 5 are NEAT1 and PVT1.Other overlapping or non‐overlapping areas show no details. B, Among the five types, the histogram shows the number of different types of lncRNA transcripts. C, According to the overlapping and non‐overlapping parts of Venn diagram (A), the number of lncRNA transcripts with a single function or multiple functions is shown

FIGURE 7

LncRNA H19 regulates sensitivity to EGFR‐targeted therapy through different mechanisms. P: phosphorylated. In geftinib‐resistant lung cancer cells, H19 affects sensitivity to EGFR‐targeted therapy by modulating miR‐148b‐3p/DDAH1 axis. In erlotinib‐resistant lung cancer cells, H19 affects sensitivity to EGFR‐targeted therapy through regulating the Src‐dependent Akt signaling pathway. (Note: The lncRNA‐protein complex is regarded as a whole, and the arrows emitted by the complex in the figure represent that the complex promotes the expression of downstream target genes. The gray arrows represent up‐ or downregulation of lncRNAs or proteins)

FIGURE 8

Analysis of lncRNA and clinical applications. A, In lung cancer, tumors with migration potential activate angiogenesis. LncRNAs are released from tumor cells and circulate in the blood. B, The blood sample is drawn from patients. After the whole blood is centrifuged, the bottom of the tube is red blood cells, and lncRNAs are extracted from the supernatant. C, Reverse transcription and amplification of cDNA by PCR. D, Clinical applications of lncRNAs in lung cancer