Open Access

Cervical cancer stem cell‑associated genes: Prognostic implications in cervical cancer (Review)

  • Authors:
    • Jorge Organista‑Nava
    • Yazmín Gómez‑Gómez
    • Olga Lilia Garibay‑Cerdenares
    • Marco Antonio Leyva‑Vázquez
    • Berenice Illades‑Aguiar
  • View Affiliations

  • Published online on: May 3, 2019     https://doi.org/10.3892/ol.2019.10307
  • Pages: 7-14
  • Copyright: © Organista‑Nava et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cervical cancer is the fourth most common type of gynecological malignancy to affect females, worldwide. Although high‑risk human papillomavirus (HR‑HPV) infection is the primary etiologic agent associated with the development of cervical cancer, cancer stem cells (CSCs) also serve a prominent role in the development, metastasis, recurrence and prognosis of the disease. CSCs are a small subpopulation of cells that have the ability to self‑renew and are present in the majority of tumors, including cervical cancer. Studies describing the phenotype of cervical CSCs (CCSCs) vary in their definition of the expression pattern of principal biomarkers, including Musashi‑1, aldehyde dehydrogenase 1, Oct3/4, Sox2 and CD49f. However, these markers are not observed in all cancers, although several may be present in multiple tumor types. The present review describes the potential biomarkers of CSCs in cervical cancer. These CCSC biomarkers may serve as molecular targets to enhance the efficacy and reduce the side effects associated with chemotherapeutic treatment in HR‑HPV‑positive cervical cancer.

Introduction

Cervical cancer is the fourth most common type of gynecological malignancy worldwide and has a high mortality rate, particularly in developing countries (1). High-risk human papillomavirus (HR-HPV) has been identified as the primary etiologic agent associated with the development of cervical cancer (2), and the most prevalent HR-HPV types are HPH-16 and HPV-18, accounting for 70% of cervical cancer cases (3). Currently, the principal challenge in clinical cancer treatment is the resistance of cancer cells to various chemotherapeutic drugs. Cervical cancers harboring HPV are known to exhibit a poor response to treatment with chemotherapeutic agents, and display impaired chemotherapy-induced apoptosis (4).

In the cervical epithelium, the transformation zone (TZ) is a niche of cells with a unique expression profile and embryonic characteristics (57). The target cells for HR-HPV infection are cuboidal epithelial cells within the TZ (considered to be the stem cells of the cervical epithelium), which are involved, in malignant transformation (Fig. 1) (6,7).

Cancer stem cells (CSCs) are a small subpopulation of tumor cells with self-renewal capacity, which maintain tumor growth and cell differentiation. Cell surface markers and transcription factors, including CD44, aldehyde dehydrogenase 1 (ALDH1), Nanog and Oct4, have been used to isolate and enrich CSC populations from different tumors, including cervical cancer (810). CSCs contribute to the tumorigenic potential of cancer, including spherogenesis, and resistance to cytotoxic drugs and ionizing radiation (11).

The strategies by which HR-HPV promotes cancer development involve the overexpression of the viral oncoproteins E6 and E7 (12). Recently, it was reported that HPV16 E7 may contribute to the transcriptional upregulation of Oct3/4 and stemness-related genes. HPV16 E7 upregulates Oct3/4, Sox2, Nanog and fibroblast growth factor 4 expression levels to maintain the self-renewal capacity of CSCs (Fig. 1) (13). Additionally, recurrence in patients with cervical cancer following treatment may be explained by the hierarchy theory of carcinogenesis, which suggests that only CSCs have tumor initiating capacity. It has also been observed that CSCs are associated with tumor metastasis, relapse and chemo/radio-resistance, resulting in unsuccessful treatment outcomes (10,14). The present review discusses the role of cervical CSCs as it is currently understood, and how they potentially represent therapeutic targets to improve the treatment of cervical cancer.

HR-HPV-mediated network regulation of CSCs in cervical cancer

In the TZ of the cervical epithelium, squamous and columnar cervical neoplasia are initiated by HR-HPV infection, where the virus targets cells that express such surface markers as CD44, CD49f, CK17 and CD133 on the cell membrane; these cells are considered to be the stem cells of the cervical epithelium (8,10,1517) (Figs. 1 and 2).

During HR-HPV infection of the target cells, viruses bind to receptors on the cell surface, resulting in virus internalization. Viral DNA is released and transported through the endosomes and endo/lysosomes to the cell nucleus (18,19). Subsequently, viral oncoprotein synthesis (including that of E6 and E7) is initiated. E7 and E6 promote the proliferation of infected stem cells by inactivation of the endogenous tumor suppressor proteins retinoblastoma-associated protein (pRb) and p53, respectively (20). The degradation of pRb terminates Sox2 and Oct3/4 repression (21). Likewise, the degradation of p53 by HR-HPV E6 leads to increased Nanog expression levels (22).

HR-HPV oncoproteins increase the expression of stemness-related genes (Oct3/4, Nanog, Sox2 and Notch3) and promote cell self-renewal (13,23,24). It has also been observed that overexpression of stemness-related genes promotes the formation of tumors, inhibits cancer cell apoptosis, cell migration, sphere formation and chemoresistance (2529). These findings suggest that HR-HPV promotes self-renewal through the upregulation of Oct3/4, Sox2 and Nanog expression to maintain the cervical cancer stem cell (CCSC) population in cervical tumors (Fig. 2). The CCSC population is frequently resistant to chemotherapy, and stemness-related genes regulate numerous other genes; this includes certain ATP-binding cassette (ABC) transporters, which are known to be associated with drug resistance. Increased expression levels of Oct3/4, Nanog, Sox2 and Notch3 are reported to promote drug resistance in CSCs. Additionally, the expression of ABC transporters, ALDH1 and Musashi-1 (MSI1) is increased in cells with high expression levels of Oct3/4-Nanog, Sox2 and Notch3, respectively (2932). These data indicate that stemness-related genes (Oct3/4, Nanog, Sox2, Notch3) are associated with the expression of ABC, ALDH1 and MSI1, which may promote the clonogenicity, proliferation, invasiveness and chemoresistance of CSCs (Fig. 2).

Markers of CCSCs as prognostic biomarkers

Studies to identify CSCs in cervical cancer frequently use experimental strategies that involve the sorting of tumor cell subpopulations, identification of surface markers and transplantation of these cells into the appropriate animal models (33). The surface markers CD133, CD34, CD44, CD26 and CD90 are used to identify and isolate CSCs from tumor cell populations. Additionally, these cells possess metastatic, invasive and chemoresistance abilities (10,3437). Several potential cervical epithelial stem cell markers, including MSI1, ALDH1, SOX2 and CD49f, have been used to identify CCSCs (10,15). In addition to MSI1, ALDH1, SOX2, CD49f and other markers, including CD44, CD133, CK-17 and Oct3/4, have also been used to identify CCSCs (10). The presence of this sub-population may help to predict the prognosis and chemoresistance of patients with cervical cancer. Additionally, CCSCs may be used as therapeutic targets for novel drugs that may increase the effectiveness of chemotherapy in patients with chemo-resistant forms of the disease.

Musashi-1

MSI1 is an RNA-binding protein expressed in the central nervous system. Mammalian MSI1 is a prominent marker of neural stem cells and progenitor cells, is expressed in several cancer types and has various cellular functions, including cell fate decision, maintenance of the stem-cell state and differentiation. It has also been reported to act as a positive regulator of cancer progression (38,39). MSI1 is a translational regulator that has been demonstrated to be overexpressed in CCSCs (15). MSI1 expression is associated with the poor prognosis of patients with cervical squamous cell carcinoma, and is significantly correlated with CD49f expression, suggesting a functional role for these 2 proteins in cervical carcinogenesis (15). The expression of MSI1 may be used to predict the prognosis of patients with cervical cancer, thus personalized therapies directed at this protein may potentially be developed.

ALDH1

ALDH1 is a detoxifying enzyme involved in the metabolism of endogenous and exogenous aldehydes, which reduces oxidative/electrophilic stress in prokaryotic and eukaryotic organisms (40). ALDH1 is involved in cellular differentiation, proliferation, mobility, embryonic development and organ homeostasis (41). ALDH expression is associated with higher rates of cell proliferation, sphere formation, migration and tumorigenesis in cervical cancer cells (42). It has also been reported that ALDH is associated with the chemo- and radio-resistance exhibited by CSCs (10). High expression of ALDH1 is associated with poor survival in patients with cervical squamous cell carcinoma that received postoperative adjuvant chemotherapy (15); as it was observed that ALDH1 expression predicts chemoresistance and poor clinical outcome in patients with cervical cancer, ALDH1 may also be a useful prognostic biomarker (43,44). Furthermore, it was observed that knockdown of ALDH1 expression reduced the migrational ability of HeLa cells, whereas augmented expression of ALDH1 increased cell migration, indicating that ALDH1 is involved in cellular migration (45). It was also observed that CCSCs in cervosphere cultures possessed increased ALDH1 activity, which is, in turn, associated with higher tumorigenic activity (10). These results provide evidence of a link between ALDH1 expression, chemoresistance and poor clinical outcome in patients with cervical cancer.

Oct3/4

Oct3/4 is a transcription factor encoded by the POU domain class 5 transcription factor 1 gene that is involved in embryonic development, stem cell maintenance, tumor growth and metastasis (46,47). Oct3/4 has been used as a biomarker of CSCs, though it cannot be used alone without considering other genes involved in the complex CSC phenotype, including Sox2, Nanog and ALDH1 (23,48,49). Overexpression of Oct3/4 has been used to determine its role in chemoresistance to multiple drugs. For example, transfection of Oct3/4 increases cisplatin resistance in cervical cancer cell lines (50). Although there have been limited studies on the association between Oct3/4 and the prognosis of patients with cervical cancer, Shen et al (51) reported that Oct3/4 expression was associated with radiation-resistance and poor survival in squamous cell carcinoma. Likewise, Yang et al (52) and Liu et al (53) demonstrated that Oct3/4 was highly expressed in CCSCs, is associated with biological behavior, and is a prognostic factor in cervical cancer. The expression of Oct3/4 in tumor cells is also associated with resistance to radiotherapy, which is an important predictor of poor survival in patients with cervical squamous cell carcinoma (51,54). These results suggest that Oct3/4 expression is associated with poor prognosis in patients with cervical cancer.

Sox2

Sox2, a member of the SRY-related HMG-box family of transcription factors, serves a principal role in tissue development and cellular differentiation, and is associated with the stem cell phenotype. Sox2 maintains stem cell-like properties in cancer cells by interacting with other stem cell markers, including Nanog and Oct3/4 (25,55,56). The increased expression of Sox2 has been observed in a variety of tumors; however, this is not a universal finding (57,58). Sox2 expression was reported to be higher in cervical cancer cells than in normal cervical cells. It was also observed to be strongly associated with poor prognosis in patients with cervical cancer (15,51,58). Additionally, Sox2-positive cells exhibit a greater capacity for self-renewal, differentiation and tumor formation (29,59). Furthermore, Sox2 overexpression is associated with poor survival and chemo-resistance (51,58), suggesting that it may be a valuable prognostic biomarker in patients with cervical cancer.

CD49f

Integrin α6, also known as CD49f, is a biomarker commonly expressed in >30 different populations of stem cells, including certain CSC populations (6062). CD49f has also been used for the characterization of CCSC populations from cervical cancer cell lines (HeLa, SiHa, Ca Ski and C-4 l). Additionally, CD49f-positive cells exhibit a greater capacity for self-renewal, enhanced tumorigenic capabilities and increased resistance to ionizing radiation, compared with CD49f-negative cells (9,10). A high level of CD49f expression was also demonstrated in cervical tumor tissues, and is associated with the poor prognosis of patients with cervical cancer (15). Ammothumkandy et al (63) reported that CD49f expression is associated with overall survival and progression in cervical cancer. Nevertheless, further investigation is required to gain a more complete understanding of the prognostic potential of CD49f expression in cervical cancer.

CD44

CD44 is a primary adhesion molecule expression in the extracellular matrix, and is involved in various biological processes. CD44 has been reported as a stem cell and CSC marker, and demonstrated to be involved in tumor progression and metastasis (64). Furthermore, CD44 expression in cervical cancer tissues was higher compared with that in normal, non-tumorous tissues (65). CD44-positive cells exhibit a greater capacity for self-renewal in subpopulations from various cervical cancer cell lines (9,10), and CD44/CD24-positive cells exhibit radiation-resistance and possess stem cell characteristics (8); these studies suggest that CD44 expression has value as a predictive biomarker for radiation-resistance in patients with cervical cancer. Nevertheless, further research is required to confirm the prognostic significance of CD44 expression in cervical cancer.

CD133

CD133 is a glycoprotein with 5 transmembrane domains, that was initially identified in human hematopoietic stem cells (66). CD133 expression is not restricted to normal stem cells, as it has also been detected in tumors and used as a CSC biomarker (67). CD133-positive cells exhibit increased self-renewal properties, and proliferation and differentiation abilities (67,68). Recently, it was reported that CD133-positive cells exhibited increased sphere-formation capacity compared with CD133-negative cells, providing further evidence to support its use as a biomarker of CCSCs. Additionally, high CD133 expression levels were detected in cervical carcinoma tissue biopsies (69), and CD133-positive CSCs were increased in radiation-resistant patients compared with those that were sensitive to radiotherapy; these data suggest that CD133 is a phenotypic marker of CSCs in cervical carcinoma (69), and that CD133 may be a prognostic biomarker in cervical cancer.

CK-17

CK17 is a keratinocyte marker and has been observed in the basal cells of the epithelium. It is also considered to be a biomarker for cervical stem cells and CSCs (16,70). High expression of CK17 has been reported in patients with cervical cancer and is associated with the development of cervical lesions; it was also reported that CK17 expression is critical for maintaining stem cell properties (10,16,17,71). Wu et al (72) reported that the altered regulation of CK17 expression affects the initiation and tumor chemoresistance of cervical cancer, suggesting that CK17 may have value as a prognostic biomarker in patients with cervical cancer.

ABC transporters

ABC transporters are one of the largest families of transmembrane proteins. These proteins use energy derived from ATP hydrolysis to transport numerous, chemically diverse compounds, including xenobiotics, antibiotics, toxins, vitamins, steroids, lipids, ions, polysaccharides, peptides and proteins, across the plasma membrane (7375). However, these efflux mechanisms may protect cancer cells from first line cytotoxic drugs, and be responsible for resistance to chemotherapy. The most extensively characterized transporter within the ABC protein family is ATP-binding cassette sub-family B member 1 (ABCB1), which is associated with resistance to doxorubicin, paclitaxel and vincristine (75). ABCG2 is implicated in resistance to camptothecin analogues and mitoxantrone (76), and ABCC1 confers resistance to folate-based antimetabolites, anthracyclines, vinca-alkaloids and anti-androgens (77). ABC transporters are frequently overexpressed in CSCs (73,74,78). As an efflux transporter on the cell membrane, ABCG2 has been reported to confer drug resistance by expelling chemotherapeutic agents out of cancer cells, and the increased expression of this transporter has been demonstrated in CCSCs (53,79,80). These observations suggest that ABC transporters serve an important role in the maintenance of CCSCs and in chemo-resistance in cervical cancer.

On the other hand, it has been revealed that a number of compounds, including salinomycin (81), curcumin (82,83) and sulforaphane (84,85), are not affected by resistance, and reduce tumor recurrence by destroying cancer cells and CSCs. Salinomycin, an antibiotic isolated from Streptomyces albus, has been shown to destroy CSCs in different types of human cancers, most likely by interfering with ABC drug transporters, the Wnt/β-catenin signaling pathway and other pathways active in CSCs (81,86). Due to its suppression of CSC-stimulating cytokines (including IL-6, −8 and −1) curcumin has numerous cytotoxic effects on CSCs, and effects on the Wnt, Notch, Hedgehog and focal adhesion kinase signaling pathways (82,83). Sulforaphane also exhibits anticarcinogenic effects on CSCs, reducing proliferation and stimulating apoptosis of cancer cells, and interfering with numerous cell signaling pathways, including Keap1-Nrf2 signaling, the mitogen-activated protein kinase pathway and NK-κB signaling (84,85).

Conclusions

Stem cells from the TZ of the cervical epithelium are targets for HR-HPV infection, which results in a unique expression profile that promotes the transformation of these cells into CCSCs (Fig. 1). CCSCs are involved in tumor development, metastasis, recurrence, resistance to multiple chemotherapeutic drugs and poor survival in patients with cervical cancer. Markers expressed by CCSCs include MSI1, ALDH1, Oct3/4, Sox2, CD49f, CD44, CD133, CK17 and ABC transporters. These biomarkers have potential to be used as prognostic indicators and therapeutic targets in patients with cervical cancer. Development of specific drugs and/or molecules to target CCSCs may provide the basis for an innovative treatment approach for the elimination of CSCs in cervical cancer (Fig. 1). Novel therapies based on the characteristics of CSCs, making them a target within the tumor, are crucial for improving clinical responses. Therefore, understanding the biology of CSC and the mechanism of CSC-targeted therapies may facilitate the development of effective treatments for patients with cervical cancer.

Acknowledgements

Not applicable.

Funding

The present study was supported by grant from CONACYT, México (Fondo Sectorial de Investigación en Salud y Seguridad Social; grant no. 201579).

Availability of data and materials

Not applicable.

Authors' contributions

JON, YGG and OLGC collated the references and wrote this review. JON, MALV and BIA reviewed and edited the 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 

Globocan 2012, . http://globocan.iarc.frOct. 2017

2 

Paavonen J: Human papillomavirus infection and the development of cervical cancer and related genital neoplasias. Int J Infect Dis. 11 (Suppl 2):S3–S9. 2007. View Article : Google Scholar : PubMed/NCBI

3 

Senapati R, Nayak B, Kar SK and Dwibedi B: HPV genotypes co-infections associated with cervical carcinoma: Special focus on phylogenetically related and non-vaccine targeted genotypes. PLoS One. 12:e01878442017. View Article : Google Scholar : PubMed/NCBI

4 

Badaracco G, Savarese A, Micheli A, Rizzo C, Paolini F, Carosi M, Cutillo G, Vizza E, Arcangeli G and Venuti A: Persistence of HPV after radio-chemotherapy in locally advanced cervical cancer. Oncol Rep. 23:1093–1099. 2010.PubMed/NCBI

5 

Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 414:105–111. 2001. View Article : Google Scholar : PubMed/NCBI

6 

Herfs M, Yamamoto Y, Laury A, Wang X, Nucci MR, McLaughlin-Drubin ME, Münger K, Feldman S, McKeon FD, Xian W and Crum CP: A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer. Proc Natl Acad Sci USA. 109:10516–10521. 2012. View Article : Google Scholar : PubMed/NCBI

7 

Herfs M, Vargas SO, Yamamoto Y, Howitt BE, Nucci MR, Hornick JL, Mckeon FD, Xian W and Crum CP: A novel blueprint for ‘top down’ differentiation defines the cervical squamocolumnar junction during development, reproductive life, and neoplasia. J Pathol. 229:460–468. 2013. View Article : Google Scholar : PubMed/NCBI

8 

Liu H, Wang YJ, Bian L, Fang ZH, Zhang QY and Cheng JX: CD44+/CD24+ cervical cancer cells resist radiotherapy and exhibit properties of cancer stem cells. Eur Rev Med Pharmacol Sci. 20:1745–1754. 2016.PubMed/NCBI

9 

López J, Poitevin A, Mendoza-Martínez V, Pérez-Plasencia C and García-Carrancá A: Cancer-initiating cells derived from established cervical cell lines exhibit stem-cell markers and increased radioresistance. BMC Cancer. 12:482012. View Article : Google Scholar : PubMed/NCBI

10 

Ortiz-Sánchez E, Santiago-López L, Cruz-Domínguez VB, Toledo-Guzmán ME, Hernández-Cueto D, Muñiz-Hernández S, Garrido E, De León DC and García-Carrancá A: Characterization of cervical cancer stem cell-like cells: Phenotyping, stemness, and human papilloma virus co-receptor expression. Oncotarget. 7:31943–31954. 2016. View Article : Google Scholar : PubMed/NCBI

11 

Dobbin ZC and Landen CN: Isolation and characterization of potential cancer stem cells from solid human tumors-potential applications. Curr Protoc Pharmacol. 63:Unit 14.28. 2013. View Article : Google Scholar : PubMed/NCBI

12 

McLaughlin-Drubin ME, Meyers J and Munger K: Cancer associated human papillomaviruses. Curr Opin Virol. 2:459–466. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Organista-Nava J, Gómez-Gómez Y, Ocadiz-Delgado R, García-Villa E, Bonilla-Delgado J, Lagunas-Martínez A, Tapia JS, Lambert PF, García-Carrancá A and Gariglio P: The HPV16 E7 oncoprotein increases the expression of Oct3/4 and stemness-related genes and augments cell self-renewal. Virology. 499:230–242. 2016. View Article : Google Scholar : PubMed/NCBI

14 

Huang R and Rofstad EK: Cancer stem cells (CSCs), cervical CSCs and targeted therapies. Oncotarget. 8:35351–35367. 2017.PubMed/NCBI

15 

Hou T, Zhang W, Tong C, Kazobinka G, Huang X, Huang Y and Zhang Y: Putative stem cell markers in cervical squamous cell carcinoma are correlated with poor clinical outcome. BMC Cancer. 15:7852015. View Article : Google Scholar : PubMed/NCBI

16 

Martens JE, Arends J, Van Der Linden PJ, De Boer BA and Helmerhorst TJ: Cytokeratin 17 and p63 are markers of the HPV target cell, the cervical stem cell. Anticancer Res. 24:771–776. 2004.PubMed/NCBI

17 

Ikeda K, Tate G, Suzuki T and Mitsuya T: Coordinate expression of cytokeratin 8 and cytokeratin 17 immunohistochemical staining in cervical intraepithelial neoplasia and cervical squamous cell carcinoma: An immunohistochemical analysis and review of the literature. Gynecol Oncol. 108:598–602. 2008. View Article : Google Scholar : PubMed/NCBI

18 

Aksoy P, Gottschalk EY and Meneses PI: HPV entry into cells. Mutat Res Rev Mutat Res. 772:13–22. 2017. View Article : Google Scholar : PubMed/NCBI

19 

López J, Ruíz G, Organista-Nava J, Gariglio P and García-Carrancá A: Human papillomavirus infections and cancer stem cells of tumors from the uterine cervix. Open Virol J. 6:232–240. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Olivero C, Lanfredini S, Borgogna C, Gariglio M and Patel GK: HPV-induced field cancerisation: Transformation of adult tissue stem cell into cancer stem cell. Front Microbiol. 9:5462018. View Article : Google Scholar : PubMed/NCBI

21 

Kareta MS, Gorges LL, Hafeez S, Benayoun BA, Marro S, Zmoos AF, Cecchini MJ, Spacek D, Batista LF, O'Brien M, et al: Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis. Cell Stem Cell. 16:39–50. 2015. View Article : Google Scholar : PubMed/NCBI

22 

Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E and Xu Y: p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol. 7:165–171. 2005. View Article : Google Scholar : PubMed/NCBI

23 

Tyagi A, Vishnoi K, Mahata S, Verma G, Srivastava Y, Masaldan S, Roy BG, Bharti AC and Das BC: Cervical cancer stem cells selectively overexpress HPV oncoprotein E6 that controls stemness and self-renewal through upregulation of HES1. Clin Cancer Res. 22:4170–4184. 2016. View Article : Google Scholar : PubMed/NCBI

24 

Xi R, Pan S, Chen X, Hui B, Zhang L, Fu S, Li X, Zhang X, Gong T, Guo J, et al: HPV16 E6-E7 induces cancer stem-like cells phenotypes in esophageal squamous cell carcinoma through the activation of PI3K/Akt signaling pathway in vitro and in vivo. Oncotarget. 7:57050–57065. 2016. View Article : Google Scholar : PubMed/NCBI

25 

Liu K, Lin B, Zhao M, Yang X, Chen M, Gao A, Liu F, Que J and Lan X: The multiple roles for Sox2 in stem cell maintenance and tumorigenesis. Cell Signal. 25:1264–1271. 2013. View Article : Google Scholar : PubMed/NCBI

26 

Wang YD, Cai N, Wu XL, Cao HZ, Xie LL and Zheng PS: OCT4 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells by miR-125b/BAK1 pathway. Cell Death Dis. 4:e7602013. View Article : Google Scholar : PubMed/NCBI

27 

Ding Y, Yu AQ, Wang XL, Guo XR, Yuan YH and Li DS: Forced expression of Nanog with mRNA synthesized in vitro to evaluate the malignancy of HeLa cells through acquiring cancer stem cell phenotypes. Oncol Rep. 35:2643–2650. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Jeong JY, Kang H, Kim TH, Kim G, Heo JH, Kwon AY, Kim S, Jung SG and An HJ: MicroRNA-136 inhibits cancer stem cell activity and enhances the anti-tumor effect of paclitaxel against chemoresistant ovarian cancer cells by targeting Notch3. Cancer Lett. 386:168–178. 2017. View Article : Google Scholar : PubMed/NCBI

29 

Liu XF, Yang WT, Xu R, Liu JT and Zheng PS: Cervical cancer cells with positive Sox2 expression exhibit the properties of cancer stem cells. PLoS One. 9:e870922014. View Article : Google Scholar : PubMed/NCBI

30 

Yang L, Zhang X, Zhang M, Zhang J, Sheng Y, Sun X, Chen Q and Wang LX: Increased Nanog expression promotes tumor development and Cisplatin resistance in human esophageal cancer cells. Cell Physiol Biochem. 30:943–952. 2012. View Article : Google Scholar : PubMed/NCBI

31 

Jia Q, Zhang X, Deng T and Gao J: Positive correlation of Oct4 and ABCG2 to chemotherapeutic resistance in CD90(+)CD133(+) liver cancer stem cells. Cell Reprogram. 15:143–150. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Pastò A, Serafin V, Pilotto G, Lago C, Bellio C, Trusolino L, Bertotti A, Hoey T, Plateroti M, Esposito G, et al: NOTCH3 signaling regulates MUSASHI-1 expression in metastatic colorectal cancer cells. Cancer Res. 74:2106–2118. 2014. View Article : Google Scholar : PubMed/NCBI

33 

Feng D, Peng C, Li C, Zhou Y, Li M, Ling B, Wei H and Tian Z: Identification and characterization of cancer stem-like cells from primary carcinoma of the cervix uteri. Oncol Rep. 22:1129–1134. 2009.PubMed/NCBI

34 

Grasso C, Anaka M, Hofmann O, Sompallae R, Broadley K, Hide W, Berridge MV, Cebon J, Behren A and McConnell MJ: Iterative sorting reveals CD133+ and CD133-melanoma cells as phenotypically distinct populations. BMC Cancer. 16:7262016. View Article : Google Scholar : PubMed/NCBI

35 

Wang P, Gao Q, Suo Z, Munthe E, Solberg S, Ma L, Wang M, Westerdaal NA, Kvalheim G and Gaudernack G: Identification and characterization of cells with cancer stem cell properties in human primary lung cancer cell lines. PLoS One. 8:e570202013. View Article : Google Scholar : PubMed/NCBI

36 

Muraro MG, Mele V, Däster S, Han J, Heberer M, Cesare Spagnoli G and Iezzi G: CD133+, CD166+CD44+, and CD24+CD44+ phenotypes fail to reliably identify cell populations with cancer stem cell functional features in established human colorectal cancer cell lines. Stem Cells Transl Med. 1:592–603. 2012. View Article : Google Scholar : PubMed/NCBI

37 

Zakaria N, Yusoff NM, Zakaria Z, Lim MN, Baharuddin PJN, Fakiruddin KS and Yahaya B: Human non-small cell lung cancer expresses putative cancer stem cell markers and exhibits the transcriptomic profile of multipotent cells. BMC Cancer. 15:842015. View Article : Google Scholar : PubMed/NCBI

38 

Chen HY, Lin LT, Wang ML, Tsai KL, Huang PI, Yang YP, Lee YY, Chen YW, Lo WL, Lan YT, et al: Musashi-1 promotes chemoresistant granule formation by PKR/eIF2α signalling cascade in refractory glioblastoma. Biochim Biophys Acta Mol Basis Dis. 1864:1850–1861. 2018. View Article : Google Scholar : PubMed/NCBI

39 

Okano H, Imai T and Okabe M: Musashi: A translational regulator of cell fate. J Cell Sci. 115:1355–1359. 2002.PubMed/NCBI

40 

Singh S, Brocker C, Koppaka V, Chen Y, Jackson BC, Matsumoto A, Thompson DC and Vasiliou V: Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress. Free Radic Biol Med. 56:89–101. 2013. View Article : Google Scholar : PubMed/NCBI

41 

Ueda K, Ogasawara S, Akiba J, Nakayama M, Todoroki K, Ueda K, Sanada S, Suekane S, Noguchi M, Matsuoka K and Yano H: Aldehyde dehydrogenase 1 identifies cells with cancer stem cell-like properties in a human renal cell carcinoma cell line. PLoS One. 8:e754632013. View Article : Google Scholar : PubMed/NCBI

42 

Rao QX, Yao TT, Zhang BZ, Lin RC, Chen ZL, Zhou H, Wang LJ, Lu HW, Chen Q, Di N and Lin ZQ: Expression and functional role of ALDH1 in cervical carcinoma cells. Asian Pac J Cancer Prev. 13:1325–1331. 2012. View Article : Google Scholar : PubMed/NCBI

43 

Xie Q, Liang J, Rao Q, Xie X, Li R, Liu Y, Zhou H, Han J, Yao T and Lin Z: Aldehyde dehydrogenase 1 expression predicts chemoresistance and poor clinical outcomes in patients with locally advanced cervical cancer treated with neoadjuvant chemotherapy prior to radical hysterectomy. Ann Surg Oncol. 23:163–170. 2016. View Article : Google Scholar : PubMed/NCBI

44 

Yao T, Wu Z, Liu Y, Rao Q and Lin Z: Aldehyde dehydrogenase 1 (ALDH1) positivity correlates with poor prognosis in cervical cancer. J Int Med Res. 42:1038–1042. 2014. View Article : Google Scholar : PubMed/NCBI

45 

Yao T, Lu R, Li Y, Peng Y, Ding M, Xie X and Lin Z: ALDH1 might influence the metastatic capability of HeLa cells. Tumor Biol. 36:7045–7051. 2015. View Article : Google Scholar

46 

Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Schöler H and Smith A: Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 95:379–391. 1998. View Article : Google Scholar : PubMed/NCBI

47 

Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X, Bourque G, George J, Leong B, Liu J, et al: The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet. 38:431–440. 2006. View Article : Google Scholar : PubMed/NCBI

48 

Yin X, Zhang BH, Zheng SS, Gao DM, Qiu SJ, Wu WZ and Ren ZG: Coexpression of gene Oct4 and Nanog initiates stem cell characteristics in hepatocellular carcinoma and promotes epithelial-mesenchymal transition through activation of Stat3/Snail signaling. J Hematol Oncol. 8:232015. View Article : Google Scholar : PubMed/NCBI

49 

Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U and Beier CP: CD133(+) and CD133(−) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 67:4010–4015. 2007. View Article : Google Scholar : PubMed/NCBI

50 

Li SW, Wu XL, Dong CL, Xie XY, Wu JF and Zhang X: The differential expression of OCT4 isoforms in cervical carcinoma. PLoS One. 10:e01180332015. View Article : Google Scholar : PubMed/NCBI

51 

Shen L, Huang X, Xie X, Su J, Yuan J and Chen X: High expression of SOX2 and OCT4 indicates radiation resistance and an independent negative prognosis in cervical squamous cell carcinoma. J Histochem Cytochem. 62:499–509. 2014. View Article : Google Scholar : PubMed/NCBI

52 

Yang Y, Wang Y, Yin C and Li X: Clinical significance of the stem cell gene Oct-4 in cervical cancer. Tumor Biol. 35:5339–5345. 2014. View Article : Google Scholar

53 

Liu H, Wang H, Li C, Zhang T, Meng X, Zhang Y and Qian H: Spheres from cervical cancer cells display stemness and cancer drug resistance. Oncol Lett. 12:2184–2188. 2016. View Article : Google Scholar : PubMed/NCBI

54 

Villodre ES, Kipper FC, Pereira MB and Lenz G: Roles of OCT4 in tumorigenesis, cancer therapy resistance and prognosis. Cancer Treat Rev. 51:1–9. 2016. View Article : Google Scholar : PubMed/NCBI

55 

Kim BW, Cho H, Choi CH, Ylaya K, Chung JY, Kim JH and Hewitt SM: Clinical significance of OCT4 and SOX2 protein expression in cervical cancer. BMC Cancer. 15:10152015. View Article : Google Scholar : PubMed/NCBI

56 

Boumahdi S, Driessens G, Lapouge G, Rorive S, Nassar D, Le Mercier M, Delatte B, Caauwe A, Lenglez S, Nkusi E, et al: SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma. Nature. 511:246–250. 2014. View Article : Google Scholar : PubMed/NCBI

57 

Wilbertz T, Wagner P, Petersen K, Stiedl AC, Scheble VJ, Maier S, Reischl M, Mikut R, Altorki NK, Moch H, et al: SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer. Mod Pathol. 24:944–953. 2011. View Article : Google Scholar : PubMed/NCBI

58 

Stewart CJ and Crook M: SOX2 expression in cervical intraepithelial neoplasia grade 3 (CIN3) and superficially invasive (stage IA1) squamous carcinoma of the cervix. Int J Gynecol Pathol. 35:566–573. 2016. View Article : Google Scholar : PubMed/NCBI

59 

Kaufhold S, Garbán H and Bonavida B: Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication. J Exp Clin Cancer Res. 35:842016. View Article : Google Scholar : PubMed/NCBI

60 

Krebsbach PH and Villa-Diaz LG: The role of integrin α6 (CD49f) in stem cells: More than a conserved biomarker. Stem Cells and Dev. 26:1090–1099. 2017. View Article : Google Scholar

61 

Chang JY, Wang C, Jin C, Yang C, Huang Y, Liu J, McKeehan WL, D'Souza RN and Wang F: Self-renewal and multilineage differentiation of mouse dental epithelial stem cells. Stem Cell Res. 11:990–1002. 2013. View Article : Google Scholar : PubMed/NCBI

62 

Villanueva-Toledo J, Ponciano-Gómez A, Ortiz-Sánchez E and Garrido E: Side populations from cervical-cancer-derived cell lines have stem-cell-like properties. Mol Biol Rep. 41:1993–2004. 2014. View Article : Google Scholar : PubMed/NCBI

63 

Ammothumkandy A, Maliekal TT, Bose MV, Rajkumar T, Shirley S, Thejaswini B, Giri VG and Krishna S: CD66 and CD49f expressing cells are associated with distinct neoplastic phenotypes and progression in human cervical cancer. Eur J Cancer. 60:166–178. 2016. View Article : Google Scholar : PubMed/NCBI

64 

Castelli G, Pelosi E and Testa U: Liver cancer: Molecular characterization, clonal evolution and cancer stem cells. Cancers (Basel). 9(pii): E1272017. View Article : Google Scholar : PubMed/NCBI

65 

Xiao S, Zhou Y, Jiang J, Yuan L and Xue M: CD44 affects the expression level of FOS-like antigen 1 in cervical cancer tissues. Mol Med Rep. 9:1667–1674. 2014. View Article : Google Scholar : PubMed/NCBI

66 

Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG, Olweus J, Kearney J and Buck DW: AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood. 90:5002–5012. 1997.PubMed/NCBI

67 

Jang JW, Song Y, Kim SH, Kim J and Seo HR: Potential mechanisms of CD133 in cancer stem cells. Life Sci. 184:25–29. 2017. View Article : Google Scholar : PubMed/NCBI

68 

Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD and Dirks PB: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004. View Article : Google Scholar : PubMed/NCBI

69 

Javed S, Sharma BK, Sood S, Sharma S, Bagga R, Bhattacharyya S, Rayat CS, Dhaliwal L and Srinivasan R: Significance of CD133 positive cells in four novel HPV-16 positive cervical cancer-derived cell lines and biopsies of invasive cervical cancer. BMC Cancer. 18:3572018. View Article : Google Scholar : PubMed/NCBI

70 

McGowan KM and Coulombe PA: Onset of keratin 17 expression coincides with the definition of major epithelial lineages during skin development. J Cell Biol. 143:469–486. 1998. View Article : Google Scholar : PubMed/NCBI

71 

Carrilho C, Alberto M, Buane L and David L: Keratins 8, 10, 13, and 17 are useful markers in the diagnosis of human cervix carcinomas. Hum Pathol. 35:546–551. 2004. View Article : Google Scholar : PubMed/NCBI

72 

Wu L, Han L, Zhou C, Wei W, Chen X, Yi H, Wu X, Bai X, Guo S, Yu Y, et al: TGF-β1-induced CK17 enhances cancer stem cell-like properties rather than EMT in promoting cervical cancer metastasis via the ERK1/2-MZF1 signaling pathway. FEBS J. 284:3000–3017. 2017. View Article : Google Scholar : PubMed/NCBI

73 

Thomas C and Tampé R: Multifaceted structures and mechanisms of ABC transport systems in health and disease. Curr Opin Struct Biol. 51:116–128. 2018. View Article : Google Scholar : PubMed/NCBI

74 

Begicevic RR and Falasca M: ABC transporters in cancer stem cells: Beyond chemoresistance. Int J Mol Sci. 18(pii): E23622017. View Article : Google Scholar : PubMed/NCBI

75 

Shukla S, Ohnuma S and Ambudkar SV: Improving cancer chemotherapy with modulators of ABC drug transporters. Curr Drug Targets. 12:621–630. 2011. View Article : Google Scholar : PubMed/NCBI

76 

Noguchi K, Katayama K and Sugimoto Y: Human ABC transporter ABCG2/BCRP expression in chemoresistance: Basic and clinical perspectives for molecular cancer therapeutics. Pharmgenomics Pers Med. 7:53–64. 2014.PubMed/NCBI

77 

Dębska S, Owecka A, Czernek U, Szydłowska-Pazera K, Habib M and Potemski P: Transmembrane transporters ABCC-structure, function and role in multidrug resistance of cancer cells. Postepy Hig Med Dosw (Online). 65:552–561. 2011.(In Polish). View Article : Google Scholar : PubMed/NCBI

78 

Kim JK, Jeon HY and Kim H: The molecular mechanisms underlying the therapeutic resistance of cancer stem cells. Arch Pharm Res. 38:389–401. 2015. View Article : Google Scholar : PubMed/NCBI

79 

Tyagi A, Vishnoi K, Kaur H, Srivastava Y, Roy BG, Das BC and Bharti AC: Cervical cancer stem cells manifest radioresistance: Association with upregulated AP-1 activity. Sci Rep. 7:47812017. View Article : Google Scholar : PubMed/NCBI

80 

Wei ZT, Yu XW, He JX, Liu Y and Zhang SL: Characteristics of primary side population cervical cancer cells. Oncol Lett. 14:3536–3544. 2017. View Article : Google Scholar : PubMed/NCBI

81 

Zhang Y, Liu L, Li F, Wu T, Jiang H, Jiang X, Du X and Wang Y: Salinomycin exerts anticancer effects on PC-3 cells and PC-3-derived cancer stem cells in vitro and in vivo. Biomed Res Int. 2017:41016532017.PubMed/NCBI

82 

Sordillo PP and Helson L: Curcumin and cancer stem cells: Curcumin has asymmetrical effects on cancer and normal stem cells. Anticancer Res. 35:599–614. 2015.PubMed/NCBI

83 

Li Y and Zhang T: Targeting cancer stem cells by curcumin and clinical applications. Cancer Lett. 346:197–205. 2014. View Article : Google Scholar : PubMed/NCBI

84 

Liu CM, Peng CY, Liao YW, Lu MY, Tsai ML, Yeh JC, Yu CH and Yu CC: Sulforaphane targets cancer stemness and tumor initiating properties in oral squamous cell carcinomas via miR-200c induction. J Formos Med Assoc. 116:41–48. 2017. View Article : Google Scholar : PubMed/NCBI

85 

Wang X, Li Y, Dai Y, Liu Q, Ning S, Liu J, Shen Z, Zhu D, Jiang F and Li Z: Sulforaphane improves chemotherapy efficacy by targeting cancer stem cell-like properties via the miR-124/IL-6R/STAT3 axis. Sci Rep. 6:367962016. View Article : Google Scholar : PubMed/NCBI

86 

Naujokat C and Steinhart R: Salinomycin as a drug for targeting human cancer stem cells. J Biomed Biotechnol. 2012:9506582012. View Article : Google Scholar : PubMed/NCBI

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July-2019
Volume 18 Issue 1

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Spandidos Publications style
Organista‑Nava J, Gómez‑Gómez Y, Garibay‑Cerdenares OL, Leyva‑Vázquez MA and Illades‑Aguiar B: Cervical cancer stem cell‑associated genes: Prognostic implications in cervical cancer (Review). Oncol Lett 18: 7-14, 2019
APA
Organista‑Nava, J., Gómez‑Gómez, Y., Garibay‑Cerdenares, O.L., Leyva‑Vázquez, M.A., & Illades‑Aguiar, B. (2019). Cervical cancer stem cell‑associated genes: Prognostic implications in cervical cancer (Review). Oncology Letters, 18, 7-14. https://doi.org/10.3892/ol.2019.10307
MLA
Organista‑Nava, J., Gómez‑Gómez, Y., Garibay‑Cerdenares, O. L., Leyva‑Vázquez, M. A., Illades‑Aguiar, B."Cervical cancer stem cell‑associated genes: Prognostic implications in cervical cancer (Review)". Oncology Letters 18.1 (2019): 7-14.
Chicago
Organista‑Nava, J., Gómez‑Gómez, Y., Garibay‑Cerdenares, O. L., Leyva‑Vázquez, M. A., Illades‑Aguiar, B."Cervical cancer stem cell‑associated genes: Prognostic implications in cervical cancer (Review)". Oncology Letters 18, no. 1 (2019): 7-14. https://doi.org/10.3892/ol.2019.10307