Clinical and Biological Significances of LINC01940 in Gastric Cancer

doi:10.21203/rs.3.rs-2723458/v1

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Clinical and Biological Significances of LINC01940 in Gastric Cancer

https://doi.org/10.21203/rs.3.rs-2723458/v1

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Background: In recent years, long-chain non-coding RNA has attracted wide attention. In addition to playing a significant role in the genesis of cancer, it is also involved in numerous biological functions. This article aims to explore the influence of LIINC01940 on the prognosis of gastric cancer and provide new insights into it.

Methods: The expression of LINC01940 in STAD and its relationship to patients' prognoses for gastric cancer were investigated using the TCGA database. The link between LINC01940 expression and STAD patient stage was investigated. GEO, KEGG, and GSEA were used to analyze their functional differences and related enrichment pathways. The immunological correlates score was determined using immunoinfiltration analysis. Furthermore assessed was the connection between STAD patients' LINC01940 expression and medication susceptibility. And verified by in vitro experiments.

Results: LINC01940 was highly expressed in STAD, and the same results were obtained by PCR. Survival analysis and Kaplan-Meier curves found that the STAD patients with high levels of LINC01940 had a poor prognosis. And LINC01940 was an independent risk factor for the poor prognosis of STAD. Furthermore, the expression of LINC01940 is correlated with T-stage. KEGG showed that LINC01940 was related to processes of metabolic biology and GSEA was enriched for calcium signaling pathway, etc. There are strong associations between LINC01940 and the tumor immune microenvironment, as well as a negative relationship between it and the sensitivity of various anticancer drugs. LINC01940 inhibited gastric cancer cell proliferation, migration, and invasion.

Conclusion: LINC01940 is overexpressed in STAD, and it is a crucial element in the progression and development of gastric cancer.

Gastric cancer

LINC01940

Prognostic

Chemosensitivity

Immunity

At present point in time, stomach cancer, also known as gastric cancer (GC), is one of the most prevalent forms of malignant gastrointestinal tumors. In addition to being the second most common type of cancer, gastric cancer is also one of the leading causes of cancer-related death in China^[1]. As one of the countries with the highest incidence of gastric cancer in China, the early symptoms are not obvious, and the tumors are not easy to find. Therefore, most patients are already in the advanced stage or late stage when they go to see the doctor for symptoms, and some patients even lose the opportunity for surgical resection. In addition, advanced gastric cancer is easy to recur and metastasize, which leads to a poor prognosis and seriously affects the survival time of patients^[2–4]. In addition to surgery, stomach cancer is now treated with chemotherapy, targeted therapy, and immunotherapy^[5]. Although the overall survival rate of these treatments has improved significantly in decades, the overall treatment effect is still not ideal, and some cancers still lack effective treatment. It is therefore very important to identify effective treatment methods to improve early detection of gastric cancer so that clinical treatment can begin as soon as possible.

Long non-coding RNA (lncRNA) is one of the non-coding RNAs that have a length of more than 200 nucleotides. Its role in tumors has gradually attracted people's attention. In the past decades, people have devoted themselves to finding valuable factors that inhibit the proliferation, metastasis, and invasion of gastric cancer cells^[6], thereby improving the chemotherapeutic drug sensitivity of gastric cancer cells^[7], etc. Some studies have shown that tumors and their growth are caused by lncRNA that is expressed in an abnormal way^{[8, 9]}. And with the in-depth exploration of molecular mechanisms, more and more evidence show that a number of processes, include cancer metastasis, cell differentiation, invasion, and apoptosis ^[10], can be affected by lncRNA, which can regulate gene expression at the transcriptional, post-transcriptional, and epigenetic levels.

LINC01940 is a lncRNA located in Chr2: 238,919,302 − 238,926,269. Through TCGA database analysis, LINC01940 expression was observed to be considerably higher in gastric cancer than in surrounding tissues. However, the relationship between LINC01940 and the occurrence and development of gastric cancer has not been reported. Therefore, Our study seeks to explore the influence of LINC01940 on GC and its influence on the survival and prognosis of gastric cancer patients.

Methords and Materials

1、Acquisition and arrangement of relevant data

We filtered out the transcription profiling and gene expression quantification related to STAD from the TCGA database (https://portal.gdc.cancer.gov/)^[11], and downloaded 407 cases of relevant information. Through further data analysis and sorting, the final sample collection included 375 cancer tissues and 32 normal tissues. At the same time, we extracted the clinical information of 443 patients with gastric cancer from the database. And obtained 438 clinical observations after removing the unavailable data. Data is analyzed by R software^[12].

2、Analysis of differentially expressed genes (DEGs)

In the TCGA-STAD group, DEGs between tumor and normal samples of GC patients were screened using the Limma R package. The cut-off value was false detection rate (FDR)-adjusted P-value < 0.01 and log2 | FC | > 0.585.

3、Enrichment Analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG)

Using the R packages clusterProfiler, ggplot2, and enrichplot, we examined the biological functions and signaling pathways of DEG using GO and KEGG analyses^[13].

4、Gene Set Enrichment Analysis(GSEA)

Use the clusterProfiler R software package to conduct GSEA for STAD differential operations. First, compute fold change (FC) among subgroups of each gene with the Limma R package, and then arrange the input genes in descending order according to the logFC value. Finally, we obtained the most advanced marker gene set (c2.cp.kegg.symbols) from the molecular characteristics database (MSigDB) through GSEA^[14].

5、Analyses of univariate and multifactor Cox risk regression

Through univariate and multivariate Cox regression analysis, it was determined whether LINC10940 and clinicopathological features were independent risk factors for STAD^[15].

6、Chemotherapy sensitivity analysis

The Cancer Therapeutics Response Portal (CTRP, https://portals.broadinstitute.org/ctrp) is used to gather the medication sensitivity information for GC. The R software package "prophy" was utilized to evaluate the IC50 of chemotherapy drugs in various LINC01940 expression groups. Chemotherapy drug sensitivity is displayed with ggplot2^[16].

7、Immune Infiltration Analysis

Based on CIBERSORT data^[17], 22 kinds of immune cells were calculated in each STAD patient. The sum of the scores of the 22 immune cell types in each sample is 1. Further, the tumor microenvironment (TME) of each STAD patient was evaluated by ESTIMATE, and the stromal score, immune score, and ESTIMATE score were evaluated by R package^[18].

8、Cell culture

GC cell lines, including BGC823, MKN45, SGC7901, AGS, and HGC27, and a gastric mucosa cell line (GES-1) were purchased from GeneChem (Shanghai, China). Cells are cultured in growth medium that consists of PRMI 1640 (Yocon, Shanghai, China), 10% fetal bovine serum (Clark, Shanghai, China), and 100 IU/ml penicillin/streptomycin (Sigma-Aldrich, MO, USA), at 5% CO₂ and 37°C. The culture medium was changed every 48 h^[19].

9、Real-Time Quantitative PCR

With the informed consent of the Affiliated Hospital of Nantong University and the patients undergoing gastric cancer surgery and the approval of the Ethics Committee of the Affiliated Hospital of Nantong University. From the Affiliated Hospital of Nantong University, eighteen pairs of GC tissues and their corresponding normal tissues were obtained. Add proper amount of TRIzol reagent (Invitrogen) to tissues and cells to extract total RNA, and detect the expression of LINC10940 by qRT-PCR^[20]. Primers were synthesized by RIBOBIO and included LINC01940 (Forward:5′-GATGAGCCGATTCTCTTGTCC-3′, Reverse: 5′-TCTCTGAACTGGGTGCTGGAT

-3′) and GAPDH (Forward: 5′- UGACCUCAACUACAUGGUUTT-3′; Reverse: 5′- AACCAUGUAGUUGAGGUCATT-3′).

10、siRNA transfection

The small interfering(si) RNAs targeting LINC01940[si-linc01940#1(S: 5′-GGCUACAACAAAGGAACACTT-3′; AS: 5′-GUGUUCCUUUGUUGUAGCCTT-3′) and si-linc01940#2(S: 5′-GUGAAUUCCAGGAGGACACTT-3′; AS: 5′-GUGUCCUCCUGGAAUUCACTT-3′); negative control(S: 5′-UUCUCCGAACGUGUCACGUTT-3′; AS: 5′-ACGUGACACGUUCGGAGAATT-3′) were designed and obtained from GenePharma Co., Ltd. (Shanghai, China). The transfection of the above siRNA and control group into GC cells was completed using Lipofectamine™ 3000 according to relevant instructions.

11、Transwell assay

AGS and BGC823 cells (1×10⁵) are resuspended on the top of a 24-well Transwell chamber (Corning, NY), and the complete medium is placed in the lower chamber. In order to stain the cells, the upper cells were removed after 48 hours and fixed for 15 minutes in methanol. After 10 minutes, they were stained with 0.1% crystal violet. Then observe and count the migrated cells under the microscope after PBS cleaning^[20].

12、Colony formation assay

800 cells were spread on 6-well plates before and after transfection and cultured in medium for 14 days to allow colony formation. PBS was gently cleaned, fixed with 4% paraformaldehyde for 15 minutes, and dyed with 0.1% crystal violet^[21]. Cell proliferation was further calculated by colony count.

13、Cell proliferation assay

The Cell Counting Kit-8 (CCK-8) test kit detects cell growth. Inoculating cells into 96-well plates at a density of 3 x 10³ per well, the cells were cultured respectively for 24, 48, 72, 96, and 120 hours. After adding 10 µL of 10% CCK-8 solution to each well, they were incubated for 2 hours^[22]. Finally, the absorbance at 450 nm is measured with a multi-function micro-spectrometer (Thermo Fisher Scientific, USA).

14、Cell scratch assay

Take 5×10⁵ well-growing gastric cancer cells that were inoculated on the 6-well plate. When the cells had grown to cover 95% of the area of the 6-well plate, they were vertically scratched with a sterile gun head on the cell layer, washed, and cultured in serum-free medium. During 0 h and 24 h, the cell migration was observed and photographed.

15、Statistics Analysis

The link between LINC01940 expression and the target of interest was assessed using the Spearman correlation test for bioinformatics validation. To compare LINC01940 expression levels between groups or between tumor and normal tissues, paired t tests or the t test were used, depending on whether the samples were paired or not. The P-value threshold for significance was set at less than 0.05. We utilize the R packages forestplot and ggplot2 to generate pertinent graphs.

1、LINC01940 is substantially expressed in STAD and is associated with poor prognosis.

Firstly, in order to explore the expression of LINC01940 in STAD tissues, we analyzed 407 STAD samples (375 tumor samples and 32 normal samples) in the TCGA database. The results showed that LINC01940 was up-regulated in cancer tissues compared with non-cancer samples (p < 0.05; Fig. 1A, B). To confirm the expression of LINC01940 in cancer tissues, We performed real-time PCR on 20 pairs of STAD and para-carcinoma tissues to detect the expression of LINC01940 and obtained the same results as above (p < 0.05; Fig. 1C). Finally, We investigated the association between LINC01940 expression and STAD patient survival time. Patients' overall survival (OS) and progression-free survival (PFS) were inversely linked with the expression of LINC01940, according to the data (Fig. 1D, E). The diagnostic ROC curve shows that the AUC value is 0.622(Fig. 1F). We also conducted a time-related ROC analysis, and the results indicated that the AUC values for 3, 5, and 10 years were correspondingly 0.553, 0.589, and 0.718. (Fig. 1G). The results presented above indicate that LINC01940 is substantially expressed in STAD and has an effect on the prognosis of STAD patients.

2、Overexpression of LINC01940 is an independent prognostic factor for STAD.

To further evaluate the impact of LINC01940 overexpression and other clinicopathological features on the survival of STAD patients, univariate and multivariate Cox regression analysis were done (Table 1). First, we analyzed all the data from the 375 cases in the TCGA. Univariate Cox regression analysis showed that the factors influencing the poor prognosis of STAD were LINC01940 (p = 0.0161), Age (p = 0.0053), Gender (p = 0.2186), Grade (p = 0.0707), and Stage (p < 0.001). Multivariate Cox regression analysis produced a similar outcome (Fig. 2A, B). According to univariate and multivariate Cox regression results, a nomogram including Stage, Age, Grade, Gender, T classification, and M classification indicators was further established to predict the overall survival rate (OS) and Progression-free survival (PFS) at 1, 3, and 5 years (Fig. 2C, E). The calibration curve also shows that the OS rate and DFS rate in 1, 3, and 5 years are in good agreement with the predicted ratio (Fig. 2D, F). The above results show that LINC01940 is an independent risk factor for poor prognosis in STAD and has a certain predictive effect on the prognosis of patients.

Table 1

Univariate and multivariate Cox hazard regression analyses of LINC01940 in TCGA-STAD dataset.
Characteristics	Univariate cox regression analysis				Multivariate cox regression analysis
Characteristics	HR	HR.95L	HR.95H	pvalue	HR	HR.95L	HR.95H	pvalue
LINC01940	1.0620	1.0112	1.1154	0.0161	0.8824	0.6000	1.2976	0.5248
Age	1.0251	1.0074	1.0432	0.0053	0.9986	0.9812	1.0164	0.8784
Gender	1.2588	0.8724	1.8164	0.2186	1.6236	1.0781	2.4451	0.0203
Grade	1.3677	0.9739	1.9207	0.0707	1.3216	0.9130	1.9130	0.1395
Stage	1.5271	1.2356	1.8872	0.0001	1.4138	1.1257	1.7755	0.0029

3、LINC01940 expression and clinical correlation analysis

We subsequently evaluated the clinical data of STAD cases to identify a link between LINC01940 expression level and clinicopathological features. The results showed that the expression of LINC01940 increased with the progression of STAD pathological T classification (p < 0.05; Fig. 3A), but there was no significant difference in the expression level of LINC01940 in N classification, M classification, pathological stage, age, or gender (Fig. 3B-F). Our results imply that the local infiltration of STAD may be associated with the overexpression of LINC01940.

4、Analysis of LINC01940 related genes and signal pathways

We further split the 375 cancer samples into high-expression and low-expression groups using the median LINC01940 expression in the TCGA database for differential analysis since overexpression of LINC01940 is associated with the prognosis of patients with STAD. A total of 466 DEGs were obtained, and a differential factor-related heat map was drawn (Fig. 4A). Differential genes were used to conduct additional enrichment analysis of GO and KEGG. GO results showed that DEGs were closely related to molecular function, cellular components, and biological processes, for instance extracellular matrix organization, collagen fibril organization, external encapsulating structure organization, and extracellular structure organization (Fig. 4B and Supplementary Fig. 1A, B). On the other hand, the LINC01940 overexpression group genes were primarily enriched in metabolic biology processes, such as protein digestion and absorption, focal adhesion, and ECM-receptor interaction (Fig. 4C, D). Further conduct GSEA test on DEGs, We found pathways related to tumor microenvironment in the MSigDB Collection (c2.cp.kegg.symbols.gmt), including calcium signaling pathway, adipocytokine signaling pathway, neuroactive ligand receptor interaction, ECM receptor interaction and melanoma (Fig. 4E-J).

5、Correlation between LINC01940 and tumor immune invasion

Since immune cells also contribute to the development and incidence of tumors^{[23, 24]}. We created the expression profiles of 21 immune cell subsets in various tumor samples using CIBERSORT, and the percentage of immune cell subtypes that invaded the tumor was evaluated, in order to further clarify the relationship between LINC01940 expression and the immunological microenvironment. The results showed that LINC01940 was associated with M2 macrophages, plasma cells, and mast cells in the tumor microenvironment of STAD (Fig. 5A, B). At present, several studies have demonstrated that M2 macrophages can promote the occurrence and development of tumors^{[25, 26]}, which is consistent with our results. We also use the ESTIMATE algorithm to score the relationship between the three types of scoring and LINC01940 expression. The results indicated a positive correlation between the expression of LINC01940 with the ESTIMATE and Stromal scores (Fig. 5C).

6、Expression of LINC01940 and sensitivity to anti-cancer drugs

To comprehend the effect of LINC01940 expression level on anticancer medication efficacy in the treatment of STAD. By analyzing the CellMiner database, we found that the expression of LINC01940 was related to the sensitivity of most anti-cancer drugs in STAD. The Drug Predictions score decreased in the STAD with low LINC01940 expression, including the RSK inhibitor PF4708671 (Fig. 6A), the inhibitor of apoptosis proteins (IAPs) AZD5582 (Fig. 6B), and the FGFR inhibitor AZD3759 (Fig. 6C-I), indicating that the anti-tumor sensitivity of the above drugs is higher. In contrast, IGF1R_3801, JAK_8517, Foretinib, JQ1, Dasatinib, and AZD1332 are more sensitive to tumors with high LINC01940 expression.

7、LINC01940 promotes cell proliferation, invasion, and migration in STAD.

We used PCR to identify the expression of LINC01940 in several STAD cell lines in order to better assess the function of LINC01940 in STAD. The findings demonstrated that GC cells had much greater levels of LINC019040 expression than did normal cells. (Fig. 7A). To investigate the inhibitory effect of LINC01940 on GC cells proliferation, CCK8 and colony formation experiments demonstrated that after HDAC4 was knocked down by AGS and BGC823, the proliferation ability was significantly inhibited, and showed more obvious inhibition with the passage of time. (Fig. 7B-F, P < 0.05). A scratch and Transwell experiment was also conducted to further test LINC01940's ability to affect gastric cancer cell migration and invasion. After knockdown of LINC01940 by AGS and BGC823, migratory and invasion capacities were dramatically decreased relative to the control group, as determined by experimental results. (Fig. 7G-K, P < 0.05).

STAD is a common tumor of the digestive tract, with about 1 million confirmed cases and more than seven hundred thousand deaths worldwide each year^[27]. In recent years, with the development of high-throughput sequencing technology, biochips, molecular diagnosis, and other high-tech, the biological information database has become increasingly perfect, and the scientific research on stomach cancer has also made gratifying achievements. LncRNAs are non-protein-coding RNA transcripts that play a crucial role in gene regulation^[28]. However, the function of most lncRNAs is still unknown, and we need to further explore.

According to this study, LINC01940 was substantially expressed in STAD relative to para-carcinoma tissue in the TCGA database, and the same results were obtained through further validation by q-PCR. Further investigation revealed a correlation between the overexpression of LINC01940 and the poor prognosis for people with STAD. We further analyzed the impact of LINC01940 overexpression on the survival of STAD patients through clinical data. K-M curve analysis showed that the high expression of LINC01940 in STAD was negatively correlated with the OS and PFS of STAD patients. In an additional time-dependent ROC analysis, AUC values were found to be 0.553, 0.589, and 0.718 for 1, 3, and 5 years, respectively. Univariate and multivariate COX regression analysis further verified the impact of LINC01940 on the prognosis of STAD. Age, stage, and the expression of LINC01940 were all substantially correlated with the OS of STAD patients, according to a univariate COX analysis. LINC01940 was found to be an independent risk factor for STAD when subjected to multivariate COX regression analysis.

The determination of classification and staging of STAD has an extremely important guiding role in clinical treatment and has a very clear guiding significance in the determination and selection of treatment principles, treatment indications, and treatment plans^[29]. We studied the association between the expression of LINC01940 and the various stages of STAD and discovered that high expression of LINC01940 may be associated with the local infiltration of STAD. In order to further understand how LINC01940 participates in the occurrence and development of STAD, we screened out the differential genes related to LINC01940 and carried out an enrichment analysis of GSEA. The results showed that LINC01940 may participate in the calcium signaling pathway, neuroactive ligand receptor interaction, ECM receptor interaction, adipocytokine signaling pathway, and melanoma. Interestingly, calcium channels contribute significantly to the growth, migration, and invasion of gastric cancer^{[30, 31]}. In addition, extracellular matrix is also closely related to STAD^[32–34].

In addition, the study revealed that high LINC01940 expression was substantially associated with plasma cells, M2 macrophages, resting mast cells, stromal score, and ESTIMAT score in the tumor microenvironment. Among them, M2 macrophages and resting mast cells are typical immune infiltrating cells in tumors^{[35, 36]}. In order to further search for more effective drugs, we evaluated the sensitivity between LNC01940 expression level and several anti-tumor medicines using the CellMiner database. This findings revealed that PF-4708671, AZD5582, and some FGFR inhibitors are more sensitive to tumors with low-expression of LINC01940.

Finally, we further validated the biological functionality of LINC01940 in STAD through in vitro experiments. LINC01940 knockdown was to dramatically limit tumor cell proliferation, migration, and invasion through cell proliferation, translation, and cellular ablation experiments.

In this study, LINC01940 was found to be substantially expressed in STAD and to be associated with both overall survival and progression-free survival in this investigation. STAD patients with LINC01940 showed a dismal prognosis, indicating that it was an independent risk factor. Its related signal channels include ECM receptor interaction, calcium signaling pathway, neuroactive ligand receptor interaction, adipocytokine signaling pathway, and melanoma. Moreover, the sensitivity of many anticancer drugs is negatively correlated with the expression of LINC01940, which provides new insights for the treatment of STAD. Finally, In vitro experiments revealed specific effects of LINC01940 on the expansion, migration, and invasion of gastric cancer cells. However, to confirm these results, in vivo tests are necessary.

Availability of data and materials

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no conflict of interest.

Authors' contributions

Study design: MLW, JZ, YLH; Statistical analysis: MLW, SC, HXG; Manuscript editing: MLW, JZ, ML, YLH, HXG; Funding acquisition: JZ, YLH; Data collection: MLW, GZZ, HXG, SC, YLH; Experimental studies: MLW, HXG, ML, All authors read and approved the final manuscript.

Consent for publication

Not applicable.

Funding

This study was supported by National Natural Science Foundation of China (82102720).

Acknowledgments

We acknowledge all the researchers and participants to share their datasets.

Ethics approval and consent to participate

The Ethics Committee of the Nantong University Hospital approved the study in conformity with the Declaration of Helsinki. Each participant signed a written informed consent form.

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No competing interests reported.

SupplementaryFig1.tif
Supplementary Figure 1: GO analysis of differences related to LINC01940. A-B The results of GO analysis for 466 DEGs are displayed in a bar chart and bubble chart, respectively.

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Version 1