Open Access

Expression level comparison of marker genes related to early embryonic development and tumor growth

  • Authors:
    • Qiu-Chen Cai
    • Da-Lun Li
    • Ying Zhang
    • Yun-Yi Liu
    • Pei Fang
    • Si-Qin Zheng
    • Yue-Yan Zhang
    • Ya-Kun Yang
    • Chun Hou
    • Cheng-Wei Gao
    • Qi-Shun Zhu
    • Chuan-Hai Cao
  • View Affiliations

  • Published online on: October 26, 2022     https://doi.org/10.3892/ol.2022.13564
  • Article Number: 444
  • Copyright: © Cai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

In tumor research, the occurrence and origin of tumors are the fundamental problems. In the 1970s, the basic discussion of the developmental biology problem of tumors was proposed, and it was believed that tumorigenesis is closely related to developmental biology. Tumors are abnormal biological structures in organisms, and their biological behavior is very similar to that of the early embryo. Many tumor‑related genes also serve regulatory roles in the normal development and differentiation of embryos. However, it remains unclear whether gene expression in early embryos has any similarities with tumor cells. In this study, to compare the similarities and differences in gene expression between early embryos and tumor cells, reverse transcription‑quantitative PCR was conducted to determine and compare the relative expression levels of nine tumor‑related genes in the brain glioma cell line, T98G, and in the early embryo of Spodoptera litura, which is fast‑growing, low‑cost, easily accessible and easy to observe. The expression of tumor‑related genes in early embryos and the similarity of regulatory mechanisms between early embryonic development and tumor growth were explored. In conclusion, tumor growth may be regarded as an abnormal embryogenic activation that happens in the organs of adult individuals.

Introduction

The treatment and prognosis of tumors has been a major focus of research in tumor-related studies, and the study of tumor pathogenesis and mechanisms of tumorigenesis is even more difficult than the study of tumor treatment. In the 1970s, Pierce and colleagues proposed that tumors are a developmental biology problem, and he believed that tumorigenesis is closely related to developmental biology (1,2). In 1892, Lobstein and Recamier presented a fundamental discussion on whether tumors are embryonic physiological disorders and their origin (35). They argued that tumors are formed by the continuous proliferation of embryonic cells stored in the body for a long time and that there is a high degree of similarity between tumors and embryos (6). Moreover, a study has shown that genes related to tumors can affect the normal development and differentiation of cells (7). Tumors are the products of embryonic gene expression and the result of the activation and expression of numerous oncogenes in the body (7). Early studies have confirmed that interconversion between tumor cells and early embryonic cells is possible under specific conditions (8,9). In 2000, Hanahan and Weinberg (2) proposed six major characteristics of tumor cells, including unlimited replication, tissue invasion, insensitivity to growth resistance, self-sufficient growth, evasion of apoptosis and sustained angiogenesis. Subsequently, in 2011, they added four more features of tumor cells, including genomic instability, promotion of inflammation, avoidance of immune response and energy dysregulation (10). These characteristics are very similar to the biological features of early embryonic cells. For example, gene methylation and demethylation, cell implantation, functional gene expression, cellular immune evasion and other such aspects in the early embryonic growth and development are strikingly like the biological function and behavior of tumor cells (1114). Both embryonic and tumor cells can be deprogrammed to achieve a proliferative stem cell state with potential for apoptosis and invasiveness. Therefore, it is hypothesized that the set of genes expressed in tumor cells may be the same as those expressed in embryonic cells, particularly those genes involved in deprogramming, proliferation and undifferentiation (4,1521).

The present study focused on the similarity of gene expression related to early embryonic development and tumor growth. Nine factors highly associated with tumor regulation, including MYC, MYB, BCL-2, BCL-2-interacting protein 3 (BNIP3), p53, PTEN, PI3K, AKT and mTOR were selected as experimental research subjects. These nine factors occupy important positions in the large regulatory network of the body (2227). Changing of their expression may lead to changes or even loss of control of the regulatory network (22,2637). In addition, these factors are highly related to the development and growth, regulatory mechanisms and microenvironment maintenance of early embryos (4,6,17,30,3842). MYC (29,31,43), MYB (26), BCL-2 (4446), BNIP3 (47), p53 (27,48), PI3K (22,28), AKT (23,49) and mTOR (32,5053) are regarded as proto-oncogenes that serve important roles in cell proliferation and differentiation, apoptosis, cell cycle regulation and metabolic processes. In previous studies of mouse embryonic development, high mRNA and protein expression levels of these proto-oncogenes were also detected in mouse embryos. The expression of these proto-oncogenes was highly associated with the successful implantation of fertilized eggs into the uterus, which could be determined by observing whether the mice became pregnant (6,30,3842,45,5456).

The main function of the anti-oncogenic biomarker, PTEN, is to promote apoptosis and hinder cell proliferation, migration and local adhesion (57). Downregulation or loss of PTEN expression was found in a variety of tumors, such as non-small cell lung cancer and glioma (37,57). A previous study showed that PTEN has low expression levels in the zygote and blastocyst stages in early embryonic development of mice (58).

Since the early embryos used in the present study were those before gastrulation, it was impossible to obtain human or large primate early embryos due to ethical restrictions. Furthermore, retrieving the early embryos of mice could be painful for the mice (59). Therefore, the insect model was chosen in the present study. Drosophila could be a good model as much of the research on humans has been conducted with Drosophila (60). However, the eggs of Drosophila are too small to clearly distinguish the embryonic development stage within them (61).

Spodoptera litura is an omnivorous and gluttonous lepidopteran pest and is closely related to Drosophila (62). Their eggs are ideal for early embryonic studies, as they are flat and hemispherical, with a diameter of about 0.4-0.5 mm; they are yellow and white when they are newly laid, turning black before hatching, and the eggs are neatly stacked together (63,64). S. litura early embryonic development occurs between 1 and 8 h after egg laying, with the earliest divisions generally occurring at 2 h after egg laying (63,64). In the present study, the newly laid eggs of S. litura were used to analyze the expression of genes related to tumor metabolism, to understand the similarities and differences between these early embryos and tumors.

Materials and methods

Materials

Experiments involved two different cell lines, T98G human glioma (65) and human astrocyte (HA) (66), which were provided by the Kunming Institute of Zoology, Chinese Academy of Sciences (Kunming, China). The original T98G cells were purchased from American Type Culture Collection (CRL-1690) and the HA cells were purchased from ScienCell Research Laboratories, Inc. (#1800). S. litura was from the Key Laboratory of the University in Yunnan Province for International Cooperation in Intercellular Communications and Regulations, Yunnan University (Kunming, China).

S. litura breeding. S. litura were maintained in an artificial climate incubator in the following conditions: Temperature, 27±1°C; humidity, 60–80%; and 12-h light/dark cycle (67). Larvae were feed with artificial synthetic diet and adult moths were feed with 10% honey solution. The formulation of the artificial diet was the same as that used by the Key Laboratory of the University in Yunnan Province for International Cooperation in Intercellular Communications and Regulations (67). Provision of food and water was ad libitum. Both the larvae and adult moths were fed with a diet containing a large amount of water, so additional drinking water was not provided. The feed and honey solution were refreshed every 2 days. Larvae between first and sixth instar were kept in breathable boxes until pupation began. Larvae were transferred to a fine sand box for pupation. The pupae were separated from the male and female according to the position of the cloaca on the pupae. After emergence, the adult S. litura were placed in glass boxes with a 1:1 sex ratio to mate and lay eggs; they were fed with honey solution at the bottom of the boxes. The mating and spawning of the eggs were recorded. Two hours after oviposition, the eggs for RNA extraction were harvested and put into liquid nitrogen for preservation. The hemocytes of 3rd instar larvae were extracted for use as a control. The hemolymph was allowed to escape by puncturing the hematopoietic cavity from the larval gastropods and collecting it in a 1.5-ml Eppendorf tube containing 5 µl 5% reduced glutathione. After obtaining 1 ml hemolymph, it was gently pipetted and centrifuged at 10,000 × g for 5 min at 4°C. The precipitated fraction was hemocytes.

Cell culture

T98G and HA cells were thawed at 37°C, centrifuged at 500 × g for 1 min at room temperature to remove DMSO, and cultured as follows: The T98G cells were cultured at 37°C in a 5% CO2 atmosphere in Eagle's Minimum Essential Medium containing L-glutamine (Gibco; Thermo Fisher Scientific, Inc.) with the addition of 10% (v/v) fetal bovine serum (FBS) (Lonza Group Ltd.) and 1% (v/v) solution of penicillin and streptomycin (Gibco; Thermo Fisher Scientific, Inc.) (65). HA cells were cultured in HA medium containing DMEM/F12 (Gibco; Thermo Fisher Scientific, Inc.), 10% (v/v) FBS (Gibco; Thermo Fisher Scientific, Inc.), 2% B27 supplements (Gibco; Thermo Fisher Scientific, Inc), 3.5 mM glucose (Sigma-Aldrich), 10 ng/ml fibroblast growth factor 2 (Alomone Labs), 10 ng/ml epidermal growth factor (Alomone Labs), and 1% penicillin/streptomycin (Gibco; Thermo Fisher Scientific, Inc.) (66).

Reverse transcription-quantitative PCR (RT-qPCR)

Total RNA samples for qPCR were extracted with RNA extraction kit (R6934-01; Omega Bio-Tek, Inc.), reverse transcription was carried out using a PrimeScript RT reagent Kit (RR047Q; Takara Bio, Inc.) according to the manufacturer's protocol and the concentration was determined. The relative expression levels of nine tumor-related genes and β-actin in early embryos and hemocytes of S. litura, the T98G and HA cell lines were measured by qPCR using an Applied Biosystems 7500 Fast Real-Time PCR System (Thermo Fisher Scientific, Inc.). The qPCR reaction procedure was as follows: 2 min at 50°C and 10 min at 95°C to activate the enzyme; 5 sec at 95°C and 35 sec at 60°C for 40 PCR cycles; 15 sec at 95°C, 1 min at 60°C, 30 sec at 95°C and 15 sec at 60°C to determine the melt curve. mRNA levels were quantified using the 2−ΔΔCq method (68) and normalized to the internal quantitative reference gene β-actin. The primers used for T98G and HA cells are listed in Table SI, and those used for S. litura are listed in Table SII.

Artemether (ART) treatment

Hatching rate measurement, head width measurement and ART treatment were conducted under S. litura breeding conditions. Newly laid eggs of S. litura were soaked for 10 sec at 27°C in 1 ml ART solution [300 ng/µl dissolved in 0.1% (v/v)] three times each day until eggs started hatching. As a blank control, newly laid eggs were soaked for 10 sec at 27°C in 1 ml H2O, and as a negative control, newly laid eggs were soaked for 10 sec at 27°C in in 1 ml 0.1% DMSO solution. ART itself is slightly soluble in water and 0.1% DMSO was added to the solution to increase the solubility of ART, so a 0.1% DMSO negative control group was set up in this experiment. The hatching rate of eggs was counted after 2 days of treatment. For the experiment on larvae ART treatment, 270 healthy newly hatched larvae were reselected and were divided into three groups. The groups of larvae were fed with a normal diet, a diet containing 0.1% DMSO and a diet containing 300 ng/µl ART, respectively, for 14 days until they pupated. During the feeding period, the width of the larvae's head capsule was measured once a day. All ART treatment experiments included three independent replicates.

Neighbor joining (NJ) tree construction

The gene sequences of MYB, MYC, BCL-2, BNIP3, p53, PI3K, AKT, mTOR and PTEN of S. litura, Homo sapiens and 18 other invertebrates and vertebrates were downloaded from the NCBI database (https://www.ncbi.nlm.nih.gov/gene/?term=). The accession numbers of all downloaded sequences are listed in Table SIII. The FASTA file was analyzed with MEGA7.0 (69), and the systematic cluster tree was constructed by NJ.

Statistical analysis

mRNA expression levels between T98G cells and HA cells, and between early embryos and larval hemocytes were compared by unpaired Student's t-test. mRNA expression of H2O-treated, DMSO-treated and artemether (ART)-treated eggs was compared using one-way ANOVA and Tukey. The hatch rate of H2O-treated, DMSO-treated and ART-treated eggs was compared using Fisher's test. The 14-day measurements of larvae head capsule width in the H2O-treated, DMSO-treated and ART-treated larvae were compared using two-way ANOVA and Tukey. The 14-day measurements of larvae head capsule width were also compared within all three groups using two-way ANOVA and Tukey to confirm normal larval growth within the group (70). GraphPad Prism 9.0 (GraphPad Software, Inc.) was used for data analysis and graph plotting. P<0.05 was considered to indicate a statistically significant difference.

Results

Gene building sequence alignment of S. litura

As shown in Fig. 1, MYB, MYC, BCL-2, BNIP3, p53, PI3K, AKT, mTOR and PTEN genes are related between the 20 species, indicating the evolutionary developmental conservation of the nine tumor-related factors.

mRNA expression levels of tumor marker genes in T98G cells

The mRNA expression levels of eight oncogenes including MYB, MYC, BCL-2, BNIP3, p53, PI3K, AKT and mTOR in T98G and HA cells were detected (Fig. 2A-H). The results demonstrated that the mRNA expression levels of the eight oncogenes in T98G cells were significantly higher compared with that in the control group. The mRNA expression level of the anti-oncogene, PTEN, in T98G cells was significantly lower compared with that in the HA cell control group (Fig. 2I). These results demonstrated that seven of these nine genes may be excellent indicators of tumor cells. As soon as the expression of these marker genes is detected, it is possible to distinguish cells which are more like tumor cells, and which are not.

mRNA expression of tumor marker genes in early embryos and larval hemocytes of S. litura

The mRNA expression levels of the eight oncogenes (MYB, MYC, BCL-2, BNIP3, p53, PI3K, AKT and mTOR) and the anti-oncogene (PTEN) were determined in S. litura early embryos and larval hemocytes (Fig. 3). The results demonstrated that the mRNA expressions of the eight oncogenes in early embryos were significantly higher compared with that in the larval control group (Fig. 3A-H). mRNA expression of the anti-oncogene, PTEN, in early embryos was significantly lower compared with that in the larval hemocytes control group (Fig. 3I). The expression levels of these oncogenes in early embryos of S. litura showed the same trend in T98G cells, suggesting that the metabolisms of tumor cells are more like S. litura early embryos than differentiated cells such as hemocyte.

Anti-cancer drugs cause the death of eggs but not fully developed larvae

In our previous studies, ART was demonstrated to exhibit excellent antitumor effects in vitro and in vivo via targeting several oncogenes and anti-tumor genes (36,7175). The results demonstrated that the hatching rate of eggs was significantly decreased after ART treatment compared with H2O treatment and DMSO treatment (Fig. 4A). Furthermore, following ART treatment, the mRNA expression levels of PI3K, AKT, mTOR and p53 of early embryos were also significantly downregulated (Fig. 4B). However, when S. litura 1st instar larvae, which had completed their embryonic development and emerged from eggs, were fed the same concentration of ART solution for 14 days, the growth and development of larvae were not significantly affected (Fig. 4C). These results suggested that embryonic development may share some similarities with tumor cells in terms of gene expression, which can be altered by ART.

Discussion

Malignant glioma is one of the most serious tumors, yet little is known about the pathogenesis of malignant glioma and other tumors (36). The causes of tumor formation are a matter of developmental biology. In our perspective of view, oncogenic factors in the environment and oncogenes in cells may initiate the rapid cell division, an ability obtained by cells after they became embryonic stem cells to ensure survival (76). In the absence of oncogenic stimulation, the rate of cell division would be reduced. Therefore, simply looking for carcinogenic factors and cancer suppressing drugs is not a solution to the cancer treatment problems such as side effects and drug resistance. From this perspective, the present study focused mainly on the similarity of the regulatory mechanisms between early embryonic development and tumor growth.

A number of in vitro systems have been established for the study of malignant gliomas, including the well-known U87, U251 and T98G cell lines. The glioma cell line used in this study was T98G because, morphologically, it is a fibroblast and is more likely to form cell clusters, which are more similar to the cellular division and proliferation of early embryos (77). In addition, this study detected expression levels of p53. Therefore, T98G cells, which could stably express p53, was an excellent candidate (78). Since p53 in S. litura has two opposite functions of both promoting and inhibiting apoptosis (79,80), we hypothesized that it could be determined whether similar mutations had occurred in p53 in early embryos and hemocytes of S. litura using the sequences of wild-type and mutant p53 in T98G cells as a reference. However, as the mutation sites could not be accurately identified by Sanger sequencing, transcriptome, proteome and SNP analyses will be performed in future studies.

Since the early embryos used in this study were those before gastrula, it was not possible to obtain human early embryos, as it is contrary to ethics and the original intention of treating diseases. The most commonly used human embryonic cell lines are not at this stage. Therefore, human embryonic cell lines were not selected. Retrieving the early embryos of mice could also be extremely painful for mice, which should be avoided. Other vertebrates such as chicken were also considered; however, due to the lack of suitable husbandry facilities and larger breeding sites, and the difficulty and expense of obtaining other vertebrate materials, an insect model organism was finally chosen for the present research. Therefore, we chose the insect S. litura, which is closely related to Drosophila, as it grows fast, is inexpensive and is easy to obtain. Besides, S. litura lay larger eggs and it is easy to observe the embryonic stage in the eggs with a low magnification dissecting microscope (62,67). However, S. litura is mainly used for specific innate immunity studies (67,70,79,8183), and, to the best of our knowledge, this is the first time that S. litura is being used in oncology research. Therefore, organisms, such as Drosophila, are also included in the NJ tree to show that S. litura is related to Drosophila and could potentially be used in oncology research.

Nine factors highly associated with tumor regulation, including MYC, MYB, BCL-2, BNIP3, p53, PTEN, PI3K, AKT and mTOR, were selected for investigation. These nine factors occupy very important positions in the large regulatory network as changes in their expression and function may lead to changes or even loss of control of the regulatory network (2227). There is an obvious difference between the present and previous studies-the use of invertebrates as experimental materials (23,2527,29,37,45,84) According to the NJ phylogenetic trees of 20 species presented in this study, these nine tumor-related key regulators are evolutionarily conserved in these species, suggesting that their functions may also be conserved.

The results of the present study revealed high expression levels of MYC, MYB, BCL-2 and BNIP3 mRNA in T98G cells, which was also observed in early embryos. The oncogenes MYC and MYB may serve similar roles in the growth-promoting regulation mechanisms of early embryogenesis and tumor growth (25,26,29), and the oncogenes BCL-2 and BNIP3 may serve anti-apoptotic and microenvironmental roles in both early embryonic stage and tumor growth (25,46,85,86). This conclusion supports the embryogenic concept of a tumor and indicated that functional genes that serve a dominant role in the tumor and early embryos may be identical.

The high mRNA expression level of the BNIP3 in early embryos and tumor cells suggested that the microenvironment of the early embryo may be highly similar to that of a tumor. BNIP3 is a downstream target protein of hypoxia-inducible factor, HIF-1α (24). High expression of HIF-1α in hypoxic environments can directly promote the high expression of BNIP3. HIF-1α and BNIP3 serve important roles in the maintenance of the hypoxic microenvironment in early embryos and tumors (24,47,84). In a previous study, it was demonstrated that embryonic development and embryonic cell growth require a good healthy microenvironment rather than a hypoxic tumor-like microenvironment (87). Therefore, the high similarity of the microenvironment between early embryos and tumors suggests that there may be a high degree of similarity between the gene expression in early embryos and tumor cells, as the similar microenvironments are regulated by the similar expression of genes.

p53 mRNA expression in the early embryos of S. litura was also examined. Previous studies have reported that bracovirus could upregulate p53 in S. litura larval hemocytes to induce apoptosis, suggesting that p53 in hemocytes might function similarly to human wild-type p53 (67,80). However, p53 mRNA expression in early embryos of S. litura and T98G cells were higher compared with larval hemocytes and HA cells, respectively, suggesting that p53 in early embryos, consistent with tumors, lost its apoptotic function and serves a role as growth promoter (48). The high expression of p53 in early embryos suggested similarities in the expression and function of p53 between early embryos and tumors.

The expression of the anti-oncogene, PTEN mRNA in T98G cells and early embryos of S. litura exhibited the same trend of low expression, which suggested that PTEN is expressed at a very low level or not expressed at all in the early embryonic stage or in tumors, and the proapoptotic effect is inhibited. Previous studies demonstrated that PTEN expression was low in tumor cells compared with normal cells (37,57). The present results suggested that PTEN expression was also low in S. litura early embryos. The similarity of the early embryo and the tumor cell was further demonstrated by the low expression of PTEN in both compared with that in normal somatic cells.

The high expression levels of the PI3K, AKT and mTOR in early embryos and T98G cells suggested that this signaling pathway may serve an important regulatory role in both, confirming the high similarity of signaling pathway regulation between early embryos and tumors. Previous studies have demonstrated that PI3K, AKT and mTOR expression was high in tumor cells compared with normal cells (23). The present results suggested that these genes were also highly expressed in S. litura early embryos. mTOR is an important node at which multiple signaling pathways intersect and is therefore an important link in the regulatory network (23,88,89).

In the present study, the similarity in the expression trends of functionally important genes between the early embryos and tumor cells was discussed by comparing the mRNA expression levels of nine evolutionarily conserved tumor-associated regulatory factors in early embryos and T98G cell lines. In addition, when early embryos and developed larvae of S. litura were treated with artemether [It was considered a typical antitumor compound in our previous studies, which could cause apoptosis by inhibiting the expression of oncogenes such as mTOR and BCL-2 and increasing the expression of oncogenes such as PTEN in cancer cells; however, artemether has no effect on normal cells (36,7275)], our results demonstrated that artemether killed the early embryos but not the larvae. In addition, the present study revealed that the expression of oncogenes was reduced, and the expression of the anti-tumor gene was increased in S. litura early embryos after treatment with artemether, and the hatching rate of eggs was reduced, and the mortality rate increased after treatment with artemether, which was similar to the increase in apoptosis of tumor cells after treatment with artemether (36). These data suggested that gene expression and metabolism of early embryos and glioma cells are extremely similar.

The results of the present experiments preliminarily confirm the concept of the embryonic origin of tumors, and place tumors from a cancer-based perspective into the perspective of individual development and evolution, that is, tumor-related regulatory factors are used to protect and promote early embryonic development and ensure the normal growth of living individuals in the early stages of their development (4,5). However, towards the end of an individual's life, tumor-associated regulatory factors are reactivated to create an embryonic-like mechanism, which competes strongly with the host and eventually outcompetes the host (90,91). The tumor is a life-regulating mechanism that has evolved over a long period of time and has been selected by natural selection and is both the beginning and the end of life (91,92).

The present study will help to reveal the gene expression regulating early embryonic development, expand the study of tumorigenesis, enrich the discourse that tumor-associated regulators are products of individual development and population evolution, and further contribute to the exploration of the nature of life and tumors and the complex relationship between them.

Supplementary Material

Supporting Data

Acknowledgements

The authors are would like to thank Professor Li Wang for helpful discussions and revision of the manuscript (Department of Medicine, Oncological Sciences and Huntsman Cancer Institute, University of Utah, UT, USA). The authors would also like to thank Dr Xi-Cai Wang, Dr Cong-Guo Jin and Dr Xiao-qun Chen for their technical assistance (Yunnan Tumor Institute, The Third Affiliated Hospital of Kunming Medical University; Kunming, China) and Kunming Pharmaceutical Commercial Co., Ltd. for provision of the artemether.

Funding

This research was supported by The Science and Technology Project of the Yunnan Health Department (grant no. 2011WS0065) and The Research and Talent Training Open Foundation of Life Science College, Yunnan University (Grant no. 2013S213).

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Authors' contributions

QCC, QSZ and CHC conceived and designed the experiments. DLL performed the qPCR of Spodoptera litura samples and tumor cell samples. PF and YYZ bred Spodoptera litura for all experiments, harvested hemocytes and performed mRNA extraction of hemocytes. YKY and CH performed head capsule width measurement and collected all measurement data. CWG and SQZ prepared the ART solution for ART treatment of newly laid eggs and larvae and performed ART treatment of newly laid eggs. YZ and YYL analyzed all sequences, calculated genetic distances, variability and conservation between species, and constructed NJ trees in the article. QCC, DLL, YZ and YYL analyzed the data. QCC and DLL drafted the manuscript. CWG, QSZ and CHC and revised the manuscript. CWG, QSZ and CHC reviewed the manuscript. CWG, QSZ and CHC confirmed the authenticity of the data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Pierce GB: The cancer cell and its control by the embryo. Rous-Whipple Award lecture. Am J Pathol. 113:117–124. 1983.PubMed/NCBI

2 

Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar : PubMed/NCBI

3 

Krebs ET: Cancer and the embryonal hypothesis. Calif Med. 66:270–271. 1947.PubMed/NCBI

4 

Ma YL, Zhang P, Wang F, Yang JJ, Yang Z and Qin HL: The relationship between early embryo development and tumourigenesis. J Cell Mol Med. 14:2697–2701. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Cofre J and Abdelhay E: Cancer is to embryology as mutation is to genetics: Hypothesis of the cancer as embryological phenomenon. Sci World J. 2017:35780902017. View Article : Google Scholar : PubMed/NCBI

6 

Murray MJ and Lessey BA: Embryo implantation and tumor metastasis: Common pathways of invasion and angiogenesis. Semin Reprod Endocrinol. 17:275–290. 1999. View Article : Google Scholar : PubMed/NCBI

7 

Vogelstein B and Kinzler KW: Cancer genes and the pathways they control. Nat Med. 10:789–799. 2004. View Article : Google Scholar : PubMed/NCBI

8 

Williams JW III, Carlson DL, Gadson RG, Rollins-Smith L, Williams CS and McKinnell RG: Cytogenetic analysis of triploid renal carcinoma in Rana pipiens. Cytogenet Cell Genet. 64:18–22. 1993. View Article : Google Scholar : PubMed/NCBI

9 

Bignold LP, Coghlan BL and Jersmann HP: Hansemann, Boveri, chromosomes and the gametogenesis-related theories of tumours. Cell Biol Int. 30:640–644. 2006. View Article : Google Scholar : PubMed/NCBI

10 

Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI

11 

Nordstrom L, Andersson E, Kuci V, Gustavsson E, Holm K, Ringnér M, Guldberg P and Ek S: DNA methylation and histone modifications regulate SOX11 expression in lymphoid and solid cancer cells. BMC Cancer. 15:2732015. View Article : Google Scholar : PubMed/NCBI

12 

Gibadulinova A, Tothova V, Pastorek J and Pastorekova S: Transcriptional regulation and functional implication of S100P in cancer. Amino Acids. 41:885–892. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Carosella ED, Rouas-Freiss N, Tronik-Le Roux D, Moreau P and LeMaoult J: HLA-G: An immune checkpoint molecule. Adv Immunol. 127:33–144. 2015. View Article : Google Scholar : PubMed/NCBI

14 

Bagley RG, Honma N, Weber W, Boutin P, Rouleau C, Shankara S, Kataoka S, Ishida I, Roberts BL and Teicher BA: Endosialin/TEM 1/CD248 is a pericyte marker of embryonic and tumor neovascularization. Microvasc Res. 76:180–188. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Monk M and Holding C: Human embryonic genes re-expressed in cancer cells. Oncogene. 20:8085–8091. 2001. View Article : Google Scholar : PubMed/NCBI

16 

Monk M: Variation in epigenetic inheritance. Trends Genet. 6:110–114. 1990. View Article : Google Scholar : PubMed/NCBI

17 

Stojanov T and O'Neill C: In vitro fertilization causes epigenetic modifications to the onset of gene expression from the zygotic genome in mice. Biol Reprod. 64:696–705. 2001. View Article : Google Scholar : PubMed/NCBI

18 

Wrenzycki C and Niemann H: Epigenetic reprogramming in early embryonic development: Effects of in-vitro production and somatic nuclear transfer. Reprod Biomed Online. 7:649–656. 2003. View Article : Google Scholar : PubMed/NCBI

19 

Chen HM, Egan JO and Chiu JF: Regulation and activities of alpha-fetoprotein. Crit Rev Eukar Gene. 7:11–41. 1997. View Article : Google Scholar : PubMed/NCBI

20 

Wang Y and Steinbeisser H: Molecular basis of morphogenesis during vertebrate gastrulation. Cell Mol Life Sci. 66:2263–2273. 2009. View Article : Google Scholar : PubMed/NCBI

21 

Katoh M: Networking of WNT, FGF, Notch, BMP, and Hedgehog signaling pathways during carcinogenesis. Stem Cell Rev. 3:30–38. 2007. View Article : Google Scholar : PubMed/NCBI

22 

Zhou JS, Yang ZS, Cheng SY, Yu JH, Huang CJ and Feng Q: miRNA-425-5p enhances lung cancer growth via the PTEN/PI3K/AKT signaling axis. BMC Pulm Med. 20:2232020. View Article : Google Scholar : PubMed/NCBI

23 

Fattahi S, Amjadi-Moheb F, Tabaripour R, Ashrafi GH and Akhavan-Niaki H: PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond. Life Sci. 262:1185132020. View Article : Google Scholar : PubMed/NCBI

24 

Zhu L, Qi BX and Hou DR: Roles of HIF1α- and HIF2α-regulated BNIP3 in hypoxia-induced injury of neurons. Pathol Res Pract. 215:822–827. 2019. View Article : Google Scholar : PubMed/NCBI

25 

Zhang Y, Wang H, Ren C, Yu H, Fang W, Zhang N, Gao S and Hou Q: Correlation Between C-MYC, BCL-2, and BCL-6 protein expression and gene translocation as biomarkers in diagnosis and prognosis of diffuse large B-cell lymphoma. Front Pharmacol. 9:017492019. View Article : Google Scholar

26 

Mitra P: Transcription regulation of MYB: A potential and novel therapeutic target in cancer. Ann Transl Med. 6:4432018. View Article : Google Scholar : PubMed/NCBI

27 

Yue X, Zhao Y, Xu Y, Zheng M, Feng Z and Hu W: Mutant p53 in cancer: Accumulation, Gain-of-Function, and therapy. J Mol Biol. 429:1595–1606. 2017. View Article : Google Scholar : PubMed/NCBI

28 

Tang Y, Weng X, Liu C, Li X and Chen C: Hypoxia enhances activity and malignant behaviors of colorectal cancer cells through the STAT3/MicroRNA-19a/PTEN/PI3K/AKT axis. Anal Cell Pathol (Amst). 2021:41324882021.PubMed/NCBI

29 

Pennanen M, Hagstrom J, Heiskanen I, Sane T, Mustonen H, Arola J and Haglund C: C-myc expression in adrenocortical tumours. J Clin Pathol. 71:129–134. 2018. View Article : Google Scholar : PubMed/NCBI

30 

En-Wu Y, Yin-Fang W, Jin-Fang X, Guang-Wei Y, Li-Huan S and Yan-Peng D: Expressions of HIF-1α, BNIP3, LC3 in villi from with women early pregnancy missed abortion. J Zhengzhou Univ (Med Sci). 52:52017.

31 

Scognamiglio R, Cabezas-Wallscheid N, Thier MC, Altamura S, Reyes A, Prendergast ÁM, Baumgärtner D, Carnevalli LS, Atzberger A, Haas S, et al: Myc depletion induces a pluripotent dormant state mimicking diapause. Cell. 164:668–680. 2016. View Article : Google Scholar : PubMed/NCBI

32 

Mayer IA and Arteaga CL: The PI3K/AKT pathway as a target for cancer treatment. Annu Rev Med. 67:11–28. 2016. View Article : Google Scholar : PubMed/NCBI

33 

Xu LF, Wu ZP, Chen Y, Zhu QS, Hamidi S and Navab R: MicroRNA-21 (miR-21) regulates cellular proliferation, invasion, migration, and apoptosis by targeting PTEN, RECK and Bcl-2 in lung squamous carcinoma, Gejiu City, China. PLoS One. 9:e1036982014. View Article : Google Scholar : PubMed/NCBI

34 

Chen Y, Yang JL, Xue ZZ, Cai QC, Hou C, Li HJ, Zhao LX, Zhang Y, Gao CW, Cong L, et al: Effects and mechanism of microRNA-218 against lung cancer. Mol Med Rep. 23:282021.PubMed/NCBI

35 

Chen Y, Hou C, Zhao LX, Cai QC, Zhang Y, Li DL, Tang Y, Liu HY, Liu YY, Zhang YY, et al: The association of microRNA-34a with high incidence and metastasis of lung cancer in gejiu and xuanwei yunnan. Front Oncol. 11:6193462021. View Article : Google Scholar : PubMed/NCBI

36 

Zhu QS, Cao CH, Yang JL, Li HJ, Zhang Y, Cai QC, Chen Y, Gao CW, Hou C, Li X, et al: Biological effects of artemether in U251 Glioma cells. Jap J Oncol Clin Res. 2:1–10. 2021.

37 

Alvarez-Garcia V, Tawil Y, Wise HM and Leslie NR: Mechanisms of PTEN loss in cancer: It's all about diversity. Semin Cancer Biol. 59:66–79. 2019. View Article : Google Scholar : PubMed/NCBI

38 

Elahi F, Lee H, Lee J, Lee ST, Park CK, Hyun SH and Lee E: Effect of rapamycin treatment during post-activation and/or in vitro culture on embryonic development after parthenogenesis and in vitro fertilization in pigs. Reprod Domest Anim. 52:741–748. 2017. View Article : Google Scholar : PubMed/NCBI

39 

Lee GK, Shin H and Lim HJ: Rapamycin influences the efficiency of in vitro fertilization and development in the mouse: A role for autophagic activation. Asian-Australas J Anim Sci. 29:1102–1110. 2016. View Article : Google Scholar : PubMed/NCBI

40 

Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, Kiyama H, Yonezawa K and Yamanaka S: mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol. 24:6710–6718. 2004. View Article : Google Scholar : PubMed/NCBI

41 

Li Y, Yao Y, Yao B, Huang W and Yang M: Expression of apoptosis modulation gene bcl-2 and p53 in mouse preimplantation embryos. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 16:493–494,515. 2000.PubMed/NCBI

42 

Pal SK, Crowell R, Kiessling AA and Cooper GM: Expression of proto-oncogenes in mouse eggs and preimplantation embryos. Mol Reprod Dev. 35:8–15. 1993. View Article : Google Scholar : PubMed/NCBI

43 

Wang J, Ma X, Jones HM, Chan LL, Song F, Zhang W, Bae-Jump VL and Zhou C: Evaluation of the antitumor effects of c-Myc-Max heterodimerization inhibitor 100258-F4 in ovarian cancer cells. J Transl Med. 12:2262014. View Article : Google Scholar : PubMed/NCBI

44 

Chami M, Prandini A, Campanella M, Pinton P, Szabadkai G, Reed JC and Rizzuto R: Bcl-2 and bax exert opposing effects on Ca2+ signaling, which do not depend on their putative pore-forming region. J Biol Chem. 279:54581–54589. 2004. View Article : Google Scholar : PubMed/NCBI

45 

Singh R, Letai A and Sarosiek K: Regulation of apoptosis in health and disease: The balancing act of BCL-2 family proteins. Nat Rev Mol Cell Bio. 20:175–193. 2019. View Article : Google Scholar : PubMed/NCBI

46 

Radha G and Raghavan SC: BCL2: A promising cancer therapeutic target. Biochim Biophys Acta Rev Cancer. 1868:309–314. 2017. View Article : Google Scholar : PubMed/NCBI

47 

Farrall AL and Whitelaw ML: The HIF1α-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element. Oncogene. 28:3671–3680. 2009. View Article : Google Scholar : PubMed/NCBI

48 

Levine AJ and Oren M: The first 30 years of p53: Growing ever more complex. Nat Rev Cancer. 9:749–758. 2009. View Article : Google Scholar : PubMed/NCBI

49 

Lien EC, Dibble CC and Toker A: PI3K signaling in cancer: Beyond AKT. Curr Opin Cell Biol. 45:62–71. 2017. View Article : Google Scholar : PubMed/NCBI

50 

Xia Z, Gao T, Zong Y, Zhang X, Mao Y, Yuan B and Lu G: Evaluation of subchronic toxicity of GRD081, a dual PI3K/mTOR inhibitor, after 28-day repeated oral administration in Sprague-Dawley rats and beagle dogs. Food Chem Toxicol. 62:687–698. 2013. View Article : Google Scholar : PubMed/NCBI

51 

Lee DH, Szczepanski MJ and Lee YJ: Magnolol induces apoptosis via inhibiting the EGFR/PI3K/Akt signaling pathway in human prostate cancer cells. J Cell Biochem. 106:1113–1122. 2009. View Article : Google Scholar : PubMed/NCBI

52 

Chen H, Zhou L, Wu X, Li R, Wen J, Sha J and Wen X: The PI3K/AKT pathway in the pathogenesis of prostate cancer. Front Biosci (Landmark Ed). 21:1084–1091. 2016. View Article : Google Scholar : PubMed/NCBI

53 

Xu K, Liu P and Wei W: mTOR signaling in tumorigenesis. Biochim Biophys Acta. 1846:638–654. 2014.PubMed/NCBI

54 

Yan-Hong L, Yuan-Qing Y, Bing Y, Wei-Quan H and Meng-Geng Y: Expression of the proto-oncogene c-myc products in early mouse embryos. J Fourth Military Med Univ. 2:253–254. 2000.

55 

Jieping C, Clarke D and Bonifer C: Effect of c-myb on hematopoietic differentiation and shaping of embryonic stem cells in vitro. J Third Military Med Univ. 27:52005.

56 

Hu W, Feng Z, Teresky AK and Levine AJ: p53 regulates maternal reproduction through LIF. Nature. 450:721–724. 2007. View Article : Google Scholar : PubMed/NCBI

57 

Gkountakos A, Sartori G, Falcone I, Piro G, Ciuffreda L, Carbone C, Tortora G, Scarpa A, Bria E, Milella M, et al: PTEN in lung cancer: Dealing with the problem, building on new knowledge and turning the game around. Cancers (Basel). 11:11412019. View Article : Google Scholar : PubMed/NCBI

58 

Xu W: Localization and expression of PTEN during early embryonic development and its effects Northwest A & F University. 2010.

59 

Moreno-Moya JM, Ramirez L, Vilella F, Martínez S, Quiñonero A, Noguera I, Pellicer A and Simón C: Complete method to obtain, culture, and transfer mouse blastocysts nonsurgically to study implantation and development. Fertil Steril. 101:e132014. View Article : Google Scholar : PubMed/NCBI

60 

Pandey UB and Nichols CD: Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacol Rev. 63:411–436. 2011. View Article : Google Scholar : PubMed/NCBI

61 

Markow TA, Beall S and Matzkin LM: Egg size, embryonic development time and ovoviviparity in Drosophila species. J Evol Biol. 22:430–434. 2009. View Article : Google Scholar : PubMed/NCBI

62 

Cheng T, Wu J, Wu Y, Chilukuri RV, Huang L, Yamamoto K, Feng L, Li W, Chen Z, Guo H, et al: Genomic adaptation to polyphagy and insecticides in a major East Asian noctuid pest. Nat Ecol Evol. 1:1747–1756. 2017. View Article : Google Scholar : PubMed/NCBI

63 

Perveen F, Ahmed H, Abbasi FM, Siddiqui NY and Gul A: Characterization of Embryonic Stages through Variations in the Egg's Contents in Spodoptera litura. J Agricultural Sci Technol. 4:24–36. 2010.(In Chinese).

64 

Bi HL, Xu J, Tan AJ and Huang YP: CRISPR/Cas9-mediated targeted gene mutagenesis in Spodoptera litura. Insect Sci. 23:469–477. 2016. View Article : Google Scholar : PubMed/NCBI

65 

Abate M, Scotti L, Nele V, Caraglia M, Biondi M, De Rosa G, Leonetti C, Campani V, Zappavigna S and Porru M: Hybrid Self-assembling nanoparticles encapsulating zoledronic acid: A strategy for fostering their clinical use. Int J Mol Sci. 23:51382022. View Article : Google Scholar : PubMed/NCBI

66 

Yin JC, Zhang L, Ma NX, Wang Y, Lee G, Hou XY, Lei ZF, Zhang FY, Dong FP, Wu GY and Chen G: Chemical conversion of human fetal astrocytes into neurons through modulation of multiple signaling pathways. Stem Cell Rep. 12:488–501. 2019. View Article : Google Scholar : PubMed/NCBI

67 

Zhou GF, Chen CX, Cai QC, Yan X, Peng NN, Li XC, Cui JH, Han YF, Zhang Q, Meng JH, et al: Bracovirus sneaks into apoptotic bodies transmitting immunosuppressive signaling driven by integration-mediated eIF5A hypusination. Front Immunol. 13:9015932022. View Article : Google Scholar : PubMed/NCBI

68 

Rao X, Huang X, Zhou Z and Lin X: An improvement of the 2ˆ(−delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biostat Bioinforma Biomath. 3:71–85. 2013.PubMed/NCBI

69 

Kumar S, Stecher G and Tamura K: MEGA7: Molecular evolutionary genetics analysis version 7.0 for bigger datasets. Mol Biol Evol. 33:1870–1874. 2016. View Article : Google Scholar : PubMed/NCBI

70 

Kou TC, Liu YT, Li M, Yang Y, Zhang W, Cui JH, Zhang XW, Dong SM, Xu S, You S, et al: Identification of β-chain of Fo F1-ATPase in apoptotic cell population induced by Microplitis bicoloratus bracovirus and its role in the development of Spodoptera litura. Arch Insect Biochem Physiol. 952017.doi: 10.1002/arch.21389. PubMed/NCBI

71 

Wu ZP, Gao CW, Wu YG, Zhu QS, Yan Chen, Xin Liu and Chuen Liu: Inhibitive effect of artemether on tumor growth and angiogenesis in the rat C6 orthotopic brain gliomas model. Integr Cancer Ther. 8:88–92. 2009. View Article : Google Scholar : PubMed/NCBI

72 

Wu ZP, Gao CW, Wang XC, Wu YG, Zhu QS and Hu WY: Anti-tumor Effect of artemether in CT-26 colorectal cancer bearing BALB/c mice. China Cancer. 16:22007.

73 

Wu ZP, Zhu QS, Gao CW, Wang XC, Wu YG and Hu WY: Experiment of inhibitive effect of artemether in different stages on colorectal cancer growth in BALB/c mice. Chin Clin Oncol. 12:743–745. 2007.

74 

Wu ZP, Zhu QS, Wei WL, Huang J, Shen HM and Tong SY: Study on inhibit ory effects of artemet her on brain glioma growth and angiogenesis in SD rats. J Kunming Med Univ. 4:16–21. 2012.

75 

Zhu QS, Wu ZP, Gao CW, Wu YG and Wang XC: Experiment of inhibitive efect of artemether on colorectal cancer growth and angiogenesis in BALB/c mice. Chin J Cancer Prev Treat. 15:189–192. 2008.

76 

Liu G, David BT, Trawczynski M and Fessler RG: Advances in pluripotent stem cells: History, mechanisms, technologies, and applications. Stem Cell Rev Rep. 16:3–32. 2020. View Article : Google Scholar : PubMed/NCBI

77 

Morimoto T, Nakazawa T, Matsuda R, Nishimura F, Nakamura M, Yamada S, Nakagawa I, Park YS, Tsujimura T and Nakase H: Evaluation of comprehensive gene expression and NK cell-mediated killing in glioblastoma cell line-derived spheroids. Cancers (Basel). 13:48962021. View Article : Google Scholar : PubMed/NCBI

78 

Park CM, Park MJ, Kwak HJ, Moon SI, Yoo DH, Lee HC, Park IC, Rhee CH and Hong SI: Induction of p53-mediated apoptosis and recovery of chemosensitivity through p53 transduction in human glioblastoma cells by cisplatin. Int J Oncol. 28:119–125. 2006.PubMed/NCBI

79 

Li M, Pang Z, Xiao W, Liu X, Zhang Y, Yu D, Yang M, Yang Y, Hu J and Luo K: A transcriptome analysis suggests apoptosis-related signaling pathways in hemocytes of Spodoptera litura after parasitization by Microplitis bicoloratus. PLoS One. 9:e1109672014. View Article : Google Scholar : PubMed/NCBI

80 

Zhang P: A study on apoptosis in host hemocytes induced by CypD-p53 interactions promoted by parasitic Microplitis bicoloratus of Spodoptera litura. Yunnan University; 2019

81 

Dong SM, Cui JH, Zhang W, Zhang XW, Kou TC, Cai QC, Xu S, You S, Yu DS, Ding L, et al: Inhibition of translation initiation factor eIF4A is required for apoptosis mediated by Microplitis bicoloratus bracovirus. Arch Insect Biochem Physiol. 962017.doi: 10.1002/arch.21423. PubMed/NCBI

82 

Cai QC, Chen CX, Liu HY, Zhang W, Han YF, Zhang Q, Zhou GF, Xu S, Liu T, Xiao W, et al: Interactions of Vank proteins from Microplitis bicoloratus bracovirus with host Dip3 suppress eIF4E expression. Dev Comp Immunol. 118:1039942021. View Article : Google Scholar : PubMed/NCBI

83 

Chen CX, He HJ, Cai QC, Zhang W, Kou TC, Zhang XW, You S, Chen YB, Liu T, Xiao W, et al: Bracovirus-mediated innexin hemichannel closure in cell disassembly. iScience. 24:1022812021. View Article : Google Scholar : PubMed/NCBI

84 

Gorbunova AS, Yapryntseva MA, Denisenko TV and Zhivotovsky B: BNIP3 in Lung cancer: To kill or rescue? Cancers (Basel). 12:33902020. View Article : Google Scholar : PubMed/NCBI

85 

Wu Y and Tang L: Bcl-2 family proteins regulate apoptosis and epithelial to mesenchymal transition by calcium signals. Curr Pharm Des. 22:4700–4704. 2016. View Article : Google Scholar : PubMed/NCBI

86 

Dlamini Z, Tshidino SC and Hull R: Abnormalities in alternative splicing of apoptotic genes and cardiovascular diseases. Int J Mol Sci. 16:27171–27190. 2015. View Article : Google Scholar : PubMed/NCBI

87 

Gu Z, Guo J, Wang H, Wen Y and Gu Q: Bioengineered microenvironment to culture early embryos. Cell Prolif. 53:e127542020. View Article : Google Scholar : PubMed/NCBI

88 

Norambuena A, Wallrabe H, McMahon L, Silva A, Swanson E, Khan SS, Baerthlein D, Kodis E, Oddo S, Mandell JW and Bloom GS: mTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer's disease. Alzheimers Dement. 13:152–167. 2017. View Article : Google Scholar : PubMed/NCBI

89 

Song L, Liu S, Zhang L, Yao H, Gao F, Xu D and Li Q: MiR-21 modulates radiosensitivity of cervical cancer through inhibiting autophagy via the PTEN/Akt/HIF-1α feedback loop and the Akt-mTOR signaling pathway. Tumor Biol. 37:12161–12168. 2016. View Article : Google Scholar : PubMed/NCBI

90 

Somarelli JA: The hallmarks of cancer as ecologically driven phenotypes. Front Ecol Evol. 9:6615832021. View Article : Google Scholar : PubMed/NCBI

91 

Merlo LMF, Pepper JW, Reid BJ and Maley CC: Cancer as an evolutionary and ecological process. Nat Rev Cancer. 6:924–935. 2006. View Article : Google Scholar : PubMed/NCBI

92 

Dujon AM, Aktipis A, Alix-Panabieres C, Amend SR, Boddy AM, Brown JS, Capp JP, DeGregori J, Ewald P, Gatenby R, et al: Identifying key questions in the ecology and evolution of cancer. Evol Appl. 14:877–892. 2021. View Article : Google Scholar : PubMed/NCBI

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Volume 24 Issue 6

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Spandidos Publications style
Cai Q, Li D, Zhang Y, Liu Y, Fang P, Zheng S, Zhang Y, Yang Y, Hou C, Gao C, Gao C, et al: Expression level comparison of marker genes related to early embryonic development and tumor growth. Oncol Lett 24: 444, 2022
APA
Cai, Q., Li, D., Zhang, Y., Liu, Y., Fang, P., Zheng, S. ... Cao, C. (2022). Expression level comparison of marker genes related to early embryonic development and tumor growth. Oncology Letters, 24, 444. https://doi.org/10.3892/ol.2022.13564
MLA
Cai, Q., Li, D., Zhang, Y., Liu, Y., Fang, P., Zheng, S., Zhang, Y., Yang, Y., Hou, C., Gao, C., Zhu, Q., Cao, C."Expression level comparison of marker genes related to early embryonic development and tumor growth". Oncology Letters 24.6 (2022): 444.
Chicago
Cai, Q., Li, D., Zhang, Y., Liu, Y., Fang, P., Zheng, S., Zhang, Y., Yang, Y., Hou, C., Gao, C., Zhu, Q., Cao, C."Expression level comparison of marker genes related to early embryonic development and tumor growth". Oncology Letters 24, no. 6 (2022): 444. https://doi.org/10.3892/ol.2022.13564