Application of CRISPR/CAS9 in Basic Gastric Cancer Research

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1		Marilia de Arruda Cardoso Smith	--	2377	2022-11-25 18:18:18	\|
2	Format correction	Sirius Huang	Meta information modification	2377	2022-11-28 03:44:31	\|

This entry is adapted from the peer-reviewed paper 10.3390/genes13112029

Gastric cancer is the subject of clinical and basic studies due to its high incidence and mortality rates worldwide. Due to the diagnosis occurring in advanced stages and the classic treatment methodologies such as gastrectomy and chemotherapy, they are extremely aggressive and limit the quality of life of these patients. CRISPR/Cas9 is a tool that allows gene editing and has been used to explore the functions of genes related to gastric cancer, in addition to being used in the treatment of this neoplasm, greatly increasing our understanding of cancer genomics.

gastric cancer CRISPR gene editing

1. Introduction

CRISPR/CAs9 is an extremely versatile tool that can be used in the study and understanding of cancer development mechanisms and in the diagnosis and treatment of several diseases, including gastric cancer (GC) ^[1].

This technique has helped studies in several areas, such as for gastric cancer, where in 2015 the study by Gannom and colleagues used the CRISPR/Cas9 technique for the first time in GC ^[2]. This pioneering study evaluated the knockdown effect of dual-specificity mitogen-activated protein kinase 1 (MAP2K1) and the relationship of MEK-inhibitory drugs with cancer cell lines, including gastric cancer. This study was important to evidence the RAS/MAPK activation driven by MAP2K1 depletion in gastric cancer.

CRISPR is an important tool that ^[3] helps us in a simple and practical way to understand the functions of genes that are still poorly described in GC. A collection of relevant GC studies that used CRISPR/Cas9 may be found in Table 1.

Table 1. Studies performed in gastric cells using the CRISPR/Cas9 methodology.

Gene	Cell Line	CRISPR Approach	Phenotype	Gene Classification	Functional Analyzes Performed	Reference
FGFR	KATOIII, SNU16, AGS	Knockout	Cell proliferation, migration, differentiation, and cell death	Oncogene	Cell viability	^[4]
PDIA3	HFE145 e GES-1	Knockout	Stress-resonant protein.	NE	Colony formation	^[5]
ATG16L1	AGS, HeLa	Knockout	Autophagy	NE	Cell viability	^[6]
PDEF	GES, SGC, AGS	Knockout	Transcription factor	Oncogene	Proliferation, apoptosis, colony formation, migration, and invasion	^[7]
GMAN	BGC-823, SGC-7901 e MKN45, GES-1 HGC-27, MGC-803, AGS	Knockout	Metastasis.	Oncogene	Invasion assay, Cell cycle, proliferation, and colony formation	^[8]
PIWIL1	AGP01	Knockout	Cell proliferation	Oncogene	Proliferation, apoptosis, colony formation, migration, and invasion	^[9]
MicroRNA-21	TMK-1, AGS, KATO III, NCI-N87, MKN-1, MKN-28, MKN-45, SNU-1, SNU-5, SNU-216, SNU- 484, SNU-601, SNU-638, SNU-668 e SNU-719	Knockout	Regulation of prostaglandins in carcinogenesis	Oncogene	Proliferation, apoptosis, colony formation	^[10]
MRFAP1	AGS, SGC-7901	Knockout	Cell cycle	Tumor suppressor	Cell cycle, cell viability	^[11]
LMX1A	AGS primary cells C-1/GC-2	Knockout	Transcription factor	Tumor suppressor	Viability, colony formation, TUNEL (cell death)	^[12]
CEACAM	AGS, KatoIII	Knockout	Cell adhesion related to the carcinoembryonic antigen	NE	NE	^[13]
ASC	AGS, MKN1	Knockout	Proinflammatory cytokine	Oncogene	Apoptosis, colony formation assay	^[14]
PANDAR	AGS SNU-1	Knockout	LNC RNA promoter of RNA activated by damage to antisense DNA CDKN1A	Oncogene	Cell viability, proliferation, and colony formation	^[15]
GSDME	SGC-7901, MKN-45, HL-60	Knockout	Cell death by pyroptosis	Tumor suppressor	Cell Viability, LDH Release Assay, Cell Death, and Apoptosis	^[16]
REPRIMO	BGC-823, AGS GES-1	Knockout	Cell cycle	Tumor suppressor	MTT	^[17]
miR-30a	MKN45 SGC-7901 HEK293T	Knockout	Post-transcriptional regulation	Tumor suppressor	Proliferation, migration, colony formation, viability	^[18]
SPOCD1	BGC823, HGC27, MGC803, SGC7901, MKN28 GES1	Knockout	Promotes migration and apoptosis reduction in CG	Oncogene	Proliferation, colony formation, migration, and invasion	^[19]
BTN3A2	BGC823, HGC27, MGC803, SGC7901, MKN28 GES1	Knockout	Adaptive immune response	Oncogene	Proliferation, colony formation, migration, and invasion	^[19]
AEP	HEK293T, MKN45 e SGC7901	Knockout	Lysosomal protein	Oncogene	Cell viability	^[20]
MASPIN	HEK293T, MCF7, SUM159, H157	Knockin	Mammary protease serine inhibitor	Tumor suppressor	Cell viability, apoptosis, and proliferation	^[21]
REPRIMO	HEK293T, MCF7, SUM159, H157	Knockin	Cell cycle	Tumor suppressor	Cell viability, apoptosis, and proliferation	^[21]
EphB2	HGC27	Knockin	Migration and invasion	Oncogene	Cell viability, apoptosis, and proliferation	^[22]
SST	293T and BGC823	Knockout	Migration and invasion	Tumor suppressor	Cell viability, apoptosis, and proliferation	^[23]

NE: not evaluated.

2. Cell Viability and Proliferation

Needless to say, the ability of cells to proliferate rapidly and uncontrollably is a key factor in GC. Therefore, understanding these biological mechanisms and genes is extremely important for the identification of therapeutic targets. The CRISPR/Cas9-mediated knockout of apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) blocked IL18 and augmented apoptosis in human GC cells, helping to reveal a novel pro-tumorigenic ASC/IL18 signaling axis in GC cell survival and a candidate therapeutic target in this disease ^[14].

Contributing to the findings of mir-21-induced loss of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in early GC and its phenotypic consequences, another study suppressed 15-PGDH in GC cells using CRISPR/Cas9, which demonstrated increased GC cell proliferation ^[10]. Therefore, the study suggested that maintaining the 15-PGDH enzyme activity could be a strategy for preventing GC, especially in tubular adenocarcinoma.

3. Cell Cycle Control

The study of genes that influence the cell cycle allows us to identify important cellular processes that differentiate a tumor cell from a healthy cell. Aspects such as unrestrained growth without the influence of external factors, the loss of programmed cell death capacity, and also the repression of tumor suppressor genes, among other properties, are important to identify specific biomarkers and potential therapeutic targets in GC.

To demonstrate the involvement of DNA hypermethylation on the regulation of the tumor suppressor gene REPRIMO and the TP53-dependent G2 arrest mediator homolog (RPRM) in GC, Lai and collaborators ^[17] used the CRISPR/Cas9 technology to first knockdown DNA methyltransferases (DNMTs). The knockdown of DNMT3A and DNMT3B resulted in a significant increase in RPRM mRNA by decreasing the RPRM promoter methylation in GC cells, suggesting an inverse correlation between DNMT functions and RPRM gene expression. To confirm the tumor suppression role of RPRM, the authors generated RPRM-deficient GC cell lines using CRISPR/Cas9, which were further inoculated in mice. The loss of RPRM enhanced the tumor formation in the in vivo model, confirming the role of RPRM as a tumor suppressor gene in GC. This study provided information regarding the role of RPRM and its regulatory methylation mechanism in GC development with potential application as a therapeutic target.

To regain the tumor suppression gene function, a study reactivated the RPRM expression using CRISPR/dCas9 linked to VP64 and SAM effector domains in GC cell lines, showing a hypermethylated RPMR promoter and expressing very low basal levels of the gene ^[21]. As a result, a marked reduction in GC proliferation was observed. This result outlined the advantage of this combinatorial epigenome editing approach to reactivate highly methylated tumor suppressor genes as a promising therapy for GC.

Another promising tumor suppressor was described in the study by Hu and collaborators ^[11], with the knockout of the Morf4-family-associated protein 1 (MRFAP1) gene using CRISPR/Cas9 from the CG human cell lines. The researchers observed that the knockout promoted an interaction of this MLN4924 subtract with suppressed tumor proteins, such as p27, which promoted a decrease in vitality, increased cell cycle arrest, and apoptosis, data that are important to relate the gene–subtract interaction to favor improvements in cancer treatment. The study by Liu et al. ^[15] used the CRISPR/Cas9-mediated knockout of promoter of CDKN1A antisense DNA damage-activated RNA (PANDAR) and evaluated its effects on the phenotype of GC cell lines. The knockout of PANDAR suppressed the proliferative activity and colony formation in the GC cell line. It was also observed by flow cytometry that the PANDAR knockout blocks the progression of the cell cycle at the G1/S checkpoint. Through this unique pattern of transcriptional modification, PANDAR remarkably facilitated the proliferation of cancer cells, the formation of clones, and resistance to chemotherapy. Another study developed by Zhang and colleagues ^[12] used the CRISPR/Cas9-mediated knockout of LIM homeobox transcription factor 1 α (LMX1A) in GC cell lines to identify LMX1A as a primary target of miR-9. The authors that demonstrated the knockout of LMX1A increased the cell viability and cell proliferation, reinforcing the role of LMX1A as a tumor suppressor in GC.

4. Invasion and Migration

The basic mechanism of metastasis development involves several important characteristics, such as the ability of cells to detach themselves from the primary tumor site and migrate to colonize more distant sites in the organism ^[24]. Due to the lack of early diagnosis and effective therapy options for GC, a better understanding of the mechanisms involved in the metastatic process of GC is necessary. In this sense, Zhou and colleagues ^[8] used the CRISPR/Cas9-mediated knockout of gastric cancer metastasis-associated long non-coding RNA (GMAN) IncRNA and evaluated the phenotype of GC cells. The knockout of the GMAN lncRNA delayed the invasive activity of these cells. This study also showed the overlapping relationship between GMAN and ephrin A1, in which the GMAN knockout induced an ephrin A1 expression reduction. Assessing the effect of ephrin A1 knockout in GC cell lines, it reduced the ability for invasion and metastasis in in vivo experiments. Another important study was developed by Zhu and colleagues ^[19], in which a GWAS analysis was used to find low-frequency genetic variants associated with the risk of GC. The authors found two genes that contained a variant associated with GC risk, SPOC-domain-containing 1 (SPOCD1) and Butyrophilin subfamily 3 member A2 (BTN3A), and eliminated these genes using CRISPR/Cas9 in GC cell lines. The knockout of SPOCD1 and BTN3A2 inhibited cell proliferation and colony formation. To investigate the effects of SPOCD1 and BTN3A2 knockout on migration and invasion, the authors performed xenograft assays and observed a tumor growth reduction in a rat model associated with SPOCD1 knockout. On the other hand, BTN3A2 was suggested as a susceptibility gene, although no significant changes in the xenograft model were observed. Zhang et al. ^[7] demonstrated that the CRISPR/Cas9-mediated deletion of SAM-pointed domain-containing Ets transcription factor (PDEF) inhibited the apoptosis, colony formation, migration, and invasion of GC cell lines. These results confirm the involvement of PDEF in the different stages of GC development. The study by Araújo et al. ^[9] demonstrated that the CRISPR/Cas9-mediated elimination of the Piwi-like protein 1 (PIWIL1) gene decreased GC cell migration and invasion abilities, demonstrating the oncogenic role of PIWIL1. On the other hand, Chen Wei’s study ^[23] demonstrated that the CRISPR/Ca9-mediated knockout of Somatostatin (SST) significantly promoted the migration and invasion capabilities of GC cell lines. These data are essential for characterizing SST as a potential tumor suppressor in GC.

Another interesting study used the CRISPR/Cas9-mediated knockin of ephrin type-B receptor 2 (EphB2) and evaluated its functions as an independent prognostic marker in patients with GC ^[22]. The results indicated that the activation of EphB2 in GC cells increased the malignant properties of GC cells, reducing the adhesion but accelerating the migration and invasion capabilities. These results indicate that EphB2 plays a pro-tumor role in GC and has therapeutic potential to be used in this neoplasia.

5. Tumorigenesis Models

Helicobacter pylori is a Gram-negative spiral bacterium that is present in 58% of the global population ^[25]. Most individuals infected with H. pylori are asymptomatic, and the presence of this bacterium increases the risk of developing ulcers and gastric adenocarcinoma ^[26]. An interesting study was carried out by Hu and collaborators ^[8], who sought to demonstrate the mechanisms in which vitamin D3 can assist in the defense of the host by promoting an autophagic reaction in the fight against H. pylori. The results showed that there is a new pathogenic mechanism that H. pylori can survive by hiding inside the autophagosomes in the GC cells by using the CRISPR/Cas9-mediated knockout of protein disulfide-isomerase A3 (PDIA3). From this study, a new vitamin D3 signaling pathway activates the PDIA3-STAT3-MCOLN3-Ca 2+ axis to reactivate the lysosome.

The molecular mechanism by which H. pylori induces peptic ulcers or gastritis cancer is not understood, but it probably involves a combination of host genetic predisposition and bacterial virulence factors (e.g., VacA and CagA proteins) ^[25]. The vacuolating cytotoxin (VacA) is responsible for several cellular responses, such as cell vacuolization, as well as other processes such as autophagy and necrosis ^[27]. Foegeding and collaborators ^[6] inhibited autophagy by using the CRISPR/Cas9-mediated knockout of autophagy-related 16-like 1 (ATG16L1) in HeLa cells. The results showed increased VacA levels or increased vacuolization compared with the control and that the VacA degradation is independent of the autophagic activity. CagA is a virulence factor used for the detection of H. pylori and is considered an important risk factor for severe gastric diseases, including GC. Zhao and coauthors ^[13] evaluated the effects of integrin receptors and the function of cell adhesion molecule 1 receptors (CEACAM) through the cag-type IV secretion system (cag-T4SS) on the CagA translocation process through a multiple knockout of CEACAM receptors in the GC cell line. The results showed that neither the direct interaction of the components of cag-T4SS with the integrins nor any signaling event mediated by the integrin is necessary for the translocation of CagA. Furthermore, the CRISPR/Cas9 mediated the deletion of miR-30a in H. pylori infected mice, the knockout mice demonstrated that genetic editing did not affect the growth and development of the mice, and little effect was observed on the H. pylori colonization rates of the mice. Increased incidence rates of chronic gastritis, chronic atrophic gastritis, atypical hyperplasia, and other precancerous lesions and manifestations of adenocarcinoma in the antral or gastric mucosa of rats have also been reported. These data demonstrate that miR-30a plays the role of a tumor suppressor in GC ^[18].

6. Chemotherapy Response

From the development of tumor cells to create resistance to chemotherapeutic-induced cell death, the CRISPR tool has been used to discover new therapeutic targets and drugs for the treatment of GC. Wang and colleagues ^[16] used CRISPR/Cas9 to mediate the knockout of the gasdermin E (GSDME) gene in a GC cell line to assess the effect of 5-fluoracil on the induction of pyroptosis in these cells. The authors found that the GSDME deficiency changed the pyroptosis induced by 5-FU to apoptosis, characterized by shrinkage, fragmentation in apoptotic bodies, and cell death without lysis. The study by Cui and collaborators ^[20] used the CRISPR/Cas9-mediated knockout of the legumain (AEP) gene to assess the proliferative capacity of these cells in the presence of different chemotherapeutic agents. This gene has previously been shown to be an oncogene related to invasiveness and metastasis in GC. The authors demonstrated that AEP knockout GC cells caused significantly decreased proliferation after treatment with 5-FU, paclitaxel, docetaxel, and T-DM1. These data demonstrate that AEP is a potential therapeutic target for GC.

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