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Table of Contents
ORIGINAL ARTICLE
Year : 2023  |  Volume : 66  |  Issue : 2  |  Page : 103-110

MiR-598-5p inhibits breast cancer tumor growth and lung metastasis by targeting PPAPDC1A


1 Department of Breast Surgery, Affiliated Fuzhou First Hospital of Fujian Medical University; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
2 Department of Breast Surgery, Affiliated Fuzhou First Hospital of Fujian Medical University, Fuzhou, Fujian Province, China

Date of Submission21-Sep-2022
Date of Decision07-Nov-2022
Date of Acceptance23-Nov-2022
Date of Web Publication03-Apr-2023

Correspondence Address:
Dr. Hui Lin
Department of Breast Surgery, Affiliated Fuzhou First Hospital of Fujian Medical University, 190 Dadao Road, Taijiang District, Fuzhou 350009, Fujian Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cjop.CJOP-D-22-00089

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  Abstract 


This study aimed to explore the effects of PPAPDC1A on the malignant phenotype of breast cancer (BC) in vivo and in vitro. PPAPDC1A expression was examined in BC tissues and cell lines by real-time polymerase chain reaction and Western blot. In this article, cell proliferation was evaluated by Cell Counting Kit-8 assay and colony formation assay, and cell migration and invasion were evaluated by wound healing assay and transwell assays. Furthermore, in vivo cell growth and pulmonary metastasis experiments were also performed using nude mice. The results showed that compared with normal tissues and cells, the PPAPDC1A expression in BC tissues and cell lines were both significantly increased. The PPAPDC1A targeting sequence significantly inhibited the PPAPDC1A expression and cell proliferation, migration, and invasion. The results of xenograft showed that knockdown of PPAPDC1A inhibited tumor growth and lung metastasis of BC. Then, the Dual-Luciferase Reporter Assay confirmed that miR-598-5p targeted the regulation of PPAPDC1A expression. In addition, the miR-598-5p expression in BC tissues was lower than that in the normal tissues. The rescue experiment showed that PPAPDC1A overexpression reversed the inhibitory effect of miR-598-5p mimic on cell proliferation, migration, and invasion. In conclusion, PPAPDC1A was highly expressed in BC tissues and cell lines, and miR-598-5p inhibited the malignant phenotype of BC by targeting PPAPDC1A.

Keywords: Breast cancer, lung metastasis, miR-598-5p, PPAPDC1A


How to cite this article:
Guo X, Yang F, Yu L, Wen R, Zhang X, Lin H. MiR-598-5p inhibits breast cancer tumor growth and lung metastasis by targeting PPAPDC1A. Chin J Physiol 2023;66:103-10

How to cite this URL:
Guo X, Yang F, Yu L, Wen R, Zhang X, Lin H. MiR-598-5p inhibits breast cancer tumor growth and lung metastasis by targeting PPAPDC1A. Chin J Physiol [serial online] 2023 [cited 2023 Jun 5];66:103-10. Available from: https://www.cjphysiology.org/text.asp?2023/66/2/103/373583




  Introduction Top


At present, great achievements have been made in cancer treatment. Breast cancer (BC) is a public health problem around the world.[1] Although with the improvement of early diagnosis rate, the overall 5-year survival rate is more than 90%, and the recurrence and metastasis of tumors are still inevitable. With the change of lifestyle and dietary structure, the incidence rate of BC has increased year by year. In China, the incidence rate of BC is increasing year by year, seriously threatening women's physical and mental health.[2] The occurrence and development mechanism of BC are still unclear. It may be related to the expression and activity changes of various related gene products of tumor cells, and the proliferation marker Ki-67 has a significant impact on the typing and treatment of BC.[3] With the deepening of research, more and more biomarkers of BC have been found, which provide an important reference value for the early diagnosis and prognosis of BC.

Phospholipid phosphatase 4 (PPAPDC1A or PLPP4) is located on human chromosome 10q26.12 and encodes an integrated membrane phosphatase containing 271 amino acids. It belongs to the PAP2 subtype and participates in cell proliferation and movement by causing the dephosphorylation of substrates. Therefore, PPAPDC1A may be related to the development of tumors.[4],[5] According to a report, PPAPDC1A is preferentially expressed in vascular endothelial cells.[6] Through gene expression profiling chip technology, Dahl et al.[7] found that PPAPDC1A is a differentially expressed gene between normal and BC tissues. The above results show that PPAPDC1A may participate in the development of BC, but the role of PPAPDC1A on tumorigenicity of BC is not clear.

MicroRNAs (miRNAs) are a class of post-transcriptional regulators of gene expression.[8] Numerous evidences demonstrated that miRNA was involved in the pathological progress of various cancers, including BC.[9],[10] Pre-RNA was cleaved by Dicer enzyme to produce two products, miRNA-3p and miRNA-5p, respectively.[11] According to the report, miR-598 plays an important regulatory role in different cancers.[12],[13],[14] Studies indicated that miR-598-3p was significantly downregulated in BC patients' serum[15] and might suppress BC progression by targeting JAG1.[16] However, the expression and role of miR-598-5p in BC have not been reported yet.

Here, in this study, we found upregulated PPAPDC1A in BC, which exert promotive effects on BC growth in vitro and in vivo. TargetScan (https://www.targetscan.org/vert_71/) predicted that miR-598-5p interacted with PPAPDC1A. Moreover, we also found the downregulated miR-598-5p in BC, which exerts inhibitory effects on BC cell malignant phenotype through targeting PPAPDC1A. Thus, targeting PPAPDC1A may be a new approach for BC tumor growth.


  Materials and Methods Top


Breast cancer tissue collection

In this study, a total of 12 BC patients from Affiliated Fuzhou First Hospital of Fujian Medical University were recruited. This study was approved by the Ethics Committee of Affiliated Fuzhou First Hospital of Fujian Medical University (No. 202003011). All the patients signed their written informed consent. We collected the cancer and adjacent tissues, which have then been stored in liquid nitrogen.

Cell purchase and culture

The MCF-10A (human normal mammary epithelial cell line), MCF-7, and MDA-MB-231 cell (BC cell lines) were purchased from ATCC (USA). BC cell lines were grown in DMEM containing 10% fetal bovine serum (FBS) and 2% penicillin and streptomycin. The normal mammary epithelial cell line was maintained in DMEM/F12 media, which was supplemented with 5% serum, 10 μg/mL insulin, and 20 ng/mL epidermal growth factor. All the cells were cultured in an incubator with 37°C and 5% CO2.

Cell transfection and infection

The PPAPDC1A overexpression vector (PPAPDC1A OE), PPAPDC1A lentivirus short hairpin RNA (sh-PPAPDC1A), miR-598-5p mimic/inhibitor, and their negative controls were constructed by RiboBio (Guangzhou, China). Lipofectamine 3000 (Invitrogen), mimic (50 nM), inhibitor (50 nM), or vector (4.0 μg) were all diluted with 250 μL serum-free medium, combined, which then been added to the BC cell. In addition, BC cells were infected with the sh-PPAPDC1A lentivirus. We observed the infection efficiency through green fluorescent protein.

Real-time quantitative polymerase chain reaction analysis

TRIzol reagent is used to extract total RNA. The SYBR1 Green polymerase chain reaction (PCR) master mix and the miRNA quantitative real-time (qRT)-PCR Starter Kit were used to detect PPAPDC1A mRNA and miR-598-5p expression. The primer sequences used were: PPAPDC1A, 5'-CATTGAGATCGGGGTGCGAG-3' and 5'-AGGAATCTTGCCAGTGATGCT-3'; GAPDH, 5'-GATTGTTGCCATCAACGACC-3' and 5'-GTGCAGGATGCATTGCTGAC-3'; miR-598-5p, 5'-GCCGAGTACGTCATCGTTGTCA-3', 5'-CTCAACTGGTGTCGTGGA-3'; U6, 5'-CTCGCTTCGGCAGCACA-3' and 5'-AACGCTTCACGAATTTGCGT-3'.

Western blot

RIPA lysis buffer is used to extract total protein from tissues or cells. Protein samples were separated, transferred to polyvinylidene fluoride (PVDF) membrane, and then incubated with anti-PPAPDC1A (PA5-20864, Invitrogen) or anti-GAPDH. After incubation with secondary antibody, the protein expression was detected by enhanced chemiluminescence.

Cell viability analysis

Cells were seeded into 96-well plates and cultured for 0 h, 24 h, 48 h, 72 h, and 96 h. After cell treatment, 10 μL Cell Counting Kit-8 (CCK-8) solution was added into the cells and incubated for another 4 h. Cell viability was evaluated by measuring the absorbance at 450 nm.

Colony formation assay

The number of colonies was used to evaluate cell proliferation. The BC cells were seeded in 6-well plates and cultured. After 2 weeks of cell growth, cells were fixed with 4% polyformaldehyde, stained with crystal violet, and then counted the number of cell colonies under the microscope (Nikon) to calculate cell proliferation viability.

Scarification assay

Two BC cells were planted in 6-well plates for culture. After 24 h, we used a pipette to draw a straight line in the 6-well plate and used PBS to clean the exfoliated cells. The cells were then cultured at 37°C in an incubator containing 5% CO2. Zero hour and 24 h later, we take photos under Olympus microscope (Olympus, Tokyo, Japan). The wound healing rate was evaluated by measuring the width change of the scratch area. Wound healing rate = (width [0 h]−width [24 h])/width (0 h).

Invasion assays

We added 200 μL cell suspension (1 × 105 cells/mL) in the upper room (Corning, USA) covered with Matrigel (BD Biosciences, USA), and added 500 μL culture medium containing 10% FBS in the lower chamber. After 24 h of incubation, the cells in the upper chamber were fixed and stained; then, the migrated cells were imaged and counted.

Xenograft tumors

BALB/c nude mice were divided into four groups (n = 5). MCF-7 and MDA-MB-231 cells transfected with sh-PPAPDC1A or short hairpin RNA negative control (sh-NC) (2 × 106 cells) were injected into the left flank of mice. Tumor volume was measured every 5 days. Twenty-five days later, all the mice were sacrificed, and the tumors were removed for weighing. Animal experiments were approved by the Animal Ethics Committee of Affiliated Fuzhou First Hospital of Fujian Medical University.

In vivo metastasis assay

Twenty-four healthy 6–8-week-old female BALB/c nude mice were housed in a SPF facility and exposed to a 12-h light/dark cycle. After 1 week of acclimatization, under isoflurane anesthesia, BC cells (2 × 106) stably transfected with sh-PPAPDC1A or sh-NC were injected through the tail vein. After 8 weeks of injection, the mice were euthanized, and the lung metastasis of mice in each group was detected by hematoxylin and eosin (H&E) staining.

Immunohistochemistry staining and hematoxylin and eosin staining

Tumor tissue and lung tissue of mice in each group were collected and fixed in 10% formaldehyde at room temperature overnight, then embedded, and sliced. Immunohistochemical staining mainly uses the target antibody (anti-Ki-67 antibody) for the first incubation, and then uses the secondary antibody for the second incubation. Finally, DAB staining was used to observe the localization and positive expression of the target protein in the tissues. The above sections were stained according to H&E staining steps, and then, the pathological changes of the tissues were examined.

Luciferase Reporter Gene Assays

Cells were co-transfected with miR-598-p mimic or NC and the wild type (WT) or MUTPPAPDC1A 3'UTR. Then, according to the manufacturer's instructions, the Dual-Luciferase® Reporter Assay System was used to measure the luciferase activity.

Statistical analysis

All the statistical analyses were carried out using GraphPad Prism 7. Values were presented as the mean ± standard deviation. The unpaired t-test was used for comparisons between two groups, and one-way analysis of variance was adopted for multiple-group comparisons. Significance was determined using the Student's t-test, and P < 0.05 was considered statistically significant.


  Results Top


PPAPDC1A is upregulated in human breast cancer tissues and cell lines

Compared to adjacent normal tissues, we found that PPAPDC1A expression was highly expressed in BC tissues [Figure 1]a, [Figure 1]b, [Figure 1]c. At the same time, we also detected the expression of PPAPDC1A in BC cells. Compared with the normal mammary epithelial cell line (MCF-10A), the RT-qPCR and Western blot results showed that PPAPDC1A expression was also highly expressed in BC cell lines [Figure 1]d and [Figure 1]e. Based on these results, we hypothesized that PPAPDC1A might play important roles in the development of BC and represent a new target for therapeutic intervention.
Figure 1: The upregulated PPAPDC1A in human BC tissues and cell lines. (a-c) RT-qPCR and Western blot analysis of PPAPDC1A expression in human BC tissues (tumor) and the adjacent tissues (normal). (d and e) RT-qPCR and Western blot analysis of PPAPDC1A expression in human BC cell lines and the normal mammary epithelial cell line. ***P < 0.001. BC: Breast cancer, RT-qPCR: Real-time quantitative polymerase chain reaction.

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Knockdown of PPAPDC1A inhibits proliferation, migration, and invasion of breast cancer cells

To explore the function of PPAPDC1A in the proliferation, migration, and invasion of BC cell, we knocked down PPAPDC1A expression using the sh-PPAPDC1A. The RT-qPCR and Western blot results showed that the expression of PPAPDC1A was significantly decreased in BC after sh-PPAPDC1A transfection [Figure 2]a and [Figure 2]b. The CCK8 assays indicated that knockdown of PPAPDC1A could significantly inhibit the viability of BC cells [Figure 2]c and [Figure 2]d. The colony formation assay [Figure 2]e and [Figure 2]f, transwell invasion assay [Figure 2]g and [Figure 2]h, and wound healing assay [Figure 2]i and [Figure 2]j demonstrated that knockdown of PPAPDC1A inhibited proliferation, migration, and invasion of BC cells. These data suggested that knockdown of PPAPDC1A inhibited proliferation, migration, and invasion of BC cells.
Figure 2: Knockdown of PPAPDC1A inhibits proliferation, migration, and invasion of BC cells. (a and b) RT-qPCR and Western blot analysis of PPAPDC1A knockdown efficiency. (c and d) CCK8 assay evaluated the BC cell viability. (e and f) Colony formation assay measured the BC cell proliferation. (g and h) Transwell invasion test shows BC cell invasion. (i and j) Wound healing assay shows BC cell migration. *P < 0.05, **P < 0.01, ***P < 0.001. RT-qPCR: Real-time quantitative PCR, BC: Breast cancer, CCK8: Cell Counting Kit-8.

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Knockdown of PPAPDC1A inhibits tumor growth and lung metastasis of breast cancer

The in vivo experiments showed that the tumor growth was slower in the PPAPDC1A knockdown group than that in the sh-NC group [Figure 3]a, [Figure 3]b, [Figure 3]d. H&E staining analysis of tumor tissue showed that [Figure 3]e the tumor cross-sectional area, tumor cell proliferation ability, and pathological mitosis of PPAPDC1A knockout group were all gradually decreased. Moreover, the number of necrotic cells and swollen cells was increased, and different numbers of nuclear fragments were dispersed, indicating that knockdown of PPAPDC1A can inhibit tumor growth. In addition, the Ki-67 immunohistochemical results [Figure 3]f further proved our conclusion.
Figure 3: Knockdown of PPAPDC1A inhibits tumor growth and lung metastasis of BC. (a) The tumor size. (b and c) The tumor growth curve. (d) The tumor weight. (e) H&E staining of tumor tissue. (f) Ki-67 staining of tumor tissue. (g) BC cells transfected with sh-PPAPDC1A were injected into the caudal vein, respectively. After 7 weeks, the lungs of nude mice were fixed with Bouin's staining and photographed. (h) H&E of the lung tissue. *P < 0.05, **P < 0.01. BC: Breast cancer.

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Furthermore, knockdown of PPAPDC1A also inhibited BC cell metastasis in vivo [Figure 3]g. Moreover, the H&E results showed that the capillaries and interstitial small blood vessels in the lung tissue of sh-PPAPDC1A mice were dilated and congested, while lung metastasis was weakened [Figure 3]h. In conclusion, these data demonstrated that knockdown of PPAPDC1A inhibited tumor growth and lung metastasis of BC.

PPAPDC1A is the direct target of miR-598-5p in breast cancer

Using the TargetScan software, we confirmed that the PPAPDC1A was a direct target of miR-598-5p [Figure 4]a. The miR-598-5p mimic significantly inhibited luciferase activity when co-transfected with the WT-PPAPDC1A 3'UTR but without the MUT-PPAPDC1A 3'UTR [Figure 4]b and [Figure 4]c. Then, the RT-qPCR and Western blot results showed that miR-598-5p inhibitor significantly increased PPAPDC1A expression at both mRNA and protein levels, while miR-598-5p mimic significantly decreased PPAPDC1A expression at both mRNA and protein levels [Figure 4]d and [Figure 4]e. In addition, compared to adjacent normal tissues, we found that miR-598-5p expression was low expressed in BC tissues [Figure 4]f. Thus, we hypothesized that miR-598-5p might play an important role in the development of BC by directly targeting PPAPDC1A.
Figure 4: PPAPDC1A is the direct target of miR-598-5p in BC. (a) The WT and MUT binding sites of miR-598-5p in PPAPDC1A 3'UTR. (b and c) Luciferase activity of BC cells co-transfected with PPAPDC1A-WT/MUT and miR-598-5p mimics or NC mimics. (d and e) RT-qPCR and Western blot analysis of the PPAPDC1 expression. (f) RT-qPCR analysis of miR-598-5p expression in BC tumor and the normal tissues. *P < 0.05, **P < 0.01, ***P < 0.001. WT: Wild type, BC: Breast cancer.

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MiR-598-5p targeting PPAPDC1A to inhibit the malignant phenotype of breast cancer cells

Finally, we overexpressed PPAPDC1A in miR-598-5p overexpressed BC cells to investigate whether PPAPDC1A overexpression could effectively reverse the anti-cancer role of miR-598-5p mimic in BC cells. As shown in [Figure 5]a and [Figure 5]b, miR-598-5p mimic inhibited cell viability, PPAPDC1A overexpression increased cell viability, and PPAPDC1A overexpression could effectively reverse the inhibitory effect of miR-598-5p mimic on the viability of BC cells. Moreover, the colony formation assay [Figure 5]c and [Figure 5]d, transwell invasion assay [Figure 5]e and [Figure 5]f, and wound healing assay [Figure 5]g and [Figure 5]h demonstrated that miR-598-5p mimic inhibited BC cell malignant phenotype, PPAPDC1A overexpression promoted BC cell malignant phenotype, and PPAPDC1A overexpression effectively reversed the inhibitory effect of miR-598-5p mimic on malignant phenotype of BC cells. In conclusion, these results proved that miR-598-5p inhibited the malignant phenotype of BC cells by targeting PPAPDC1A.
Figure 5: MiR-598-5p inhibits the proliferation, migration, and invasion of BC cells by targeting PPAPDC1A. The BC cells were co-transfected with miR-598-5p mimic and PPAPDC1A overexpression vector (PPAPDC1A OE) or their negative controls (mimic NC and negative control overexpression vector, NC OE). (a and b) The BC cell viability evaluated by CCK8 assay. (c and d) The BC cell proliferation measured by colony formation assay. (e and f) Transwell invasion test shows BC cell invasion. (g and h) Wound healing assay shows BC cell migration. *P < 0.05, **P < 0.01, ***P < 0.001. BC: Breast cancer, CCK8: Cell Counting Kit-8.

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  Discussion Top


According to the 2021 study, BC is the major cancer of women in the world and the main cause of cancer-related mortality.[17] Due to the lack of effective treatment or prevention strategies, nearly 30% of patients have recurrence or metastasis, which is the main cause of BC-related mortality.[18] However, the molecular mechanisms that regulate and drive BC remain unclear.

The change of lipid phosphatase expression is related to the development and progress of several human cancers.[19] It is reported that PPAPDC1A is abnormally expressed in lung cancer tissues and cells. The highly expressed PPAPDC1A is positively related to the advanced clinicopathological characteristics and poor prognosis of lung cancer patients.[5] Here, our results showed that PPAPDC1A was upregulated in BC tissues and cells. This result was consistent with previous researches[4] and the supporting evidence of human cancer genome-wide analysis.[20],[21] Further functional test results proved that knockout of PPAPDC1A impaired the malignant phenotype of BC cells. In vivo experiments also confirmed that knockout of PPAPDC1A inhibited tumor growth and lung metastasis.

PPAPDC1A gene is located on human chromosome 10q26.12 and encodes an integrated membrane phosphatase containing 271 amino acids.[6] Research showed that PPAPDC1A silencing inhibits Ca2+-permeable cationic channel, suggesting that downregulation of PPAPDC1A inhibits proliferation and tumorigenesis in lung carcinoma cells through reducing the influx of intracellular Ca2+.[5] Intracellular Ca2+ dynamics shape malignant behaviors of cancer cells. The latest research showed that the resting intracellular Ca2+ concentration was elevated and acetylcholine-induced strongly augmented intracellular Ca2+ responses in BC tissue compared with normal breast tissue.[22] Therefore, we speculate that PPAPDC1A may participate in tumor growth and metastasis of BC by regulating the influx of intracellular Ca2+. Moreover, we plan to study the molecular mechanism of PPAPDC1A overexpression promoting the malignant phenotype of BC in future research.

Studies indicated that miR-598-3p was significantly downregulated in BC patients' serum[15] and might suppress BC progression by targeting JAG1.[16] Here, we found that compared to adjacent normal tissues, miR-598-5p expression was low expressed in BC tissues. Moreover, through the luciferase reporter gene experiment, we proved that PPAPDC1A was the direct target of miR-598-5p in BC. The results of rescue experiment further proved that miR-598-5p mimic could inhibit malignant phenotype of BC cells by targeting PPAPDC1A.


  Conclusion Top


To sum up, PPAPDC1A is an oncogene in BC, and miR-598-5p inhibits the malignant phenotype (proliferation, migration, and invasion) of BC cells by targeting PPAPDC1A. Thereby, targeting PPAPDC1A may be a new therapeutic strategy to inhibit the development of BC.

Financial support and sponsorship

The project was supported by the Natural Science Foundation of Fujian Province (No. 2020J011179).

Conflicts of interest

There are no conflicts of interest.



 
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