The subpopulation of CD44-positive cells promoted tumorigenicity and metastatic ability in lung adenocarcinoma

Wang, Chien‐Ying; Huang, Cheng-Yang; Yang, Yi‐Ping; Liu, Chao-Yu; Liu, Yung-Yang; Wu, Wai-Wah; Lu, Kai-Hsi; Chen, Kuan-Hsuan; Chang, Yuh‐Lih; Lee, Shou‐Dong; Lin, Hsin-Chi

doi:10.1097/jcma.0000000000000056

Cited by 26 publications

(22 citation statements)

References 28 publications

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“…By tumorsphere cultivation, the CSC activity was greater in A400 cells than that of A549 cells ( Figure 1 A). BMI1 [ 14 ], CD44 [ 22 ], or Notch1 [ 23 ] has been reported as the important positive regulator in the self-renewal capability of lung CSCs. By western blot analysis, the protein expressions of BMI1, CD44, or activated Notch1 (notch intracellular domain, NICD), were upregulated in A400 cells in comparison to parental A549 cells ( Figure 1 B).…”

Section: Resultsmentioning

confidence: 99%

BMI1-Mediated Pemetrexed Resistance in Non-Small Cell Lung Cancer Cells Is Associated with Increased SP1 Activation and Cancer Stemness

Shen

Chien

Chen

et al. 2020

Cancers

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Lung cancer is the leading cause of cancer death worldwide and the therapeutic strategies include surgery, chemotherapy and radiation therapy. Non-small cell lung cancers (NSCLCs) account for around 85% of cases of lung cancers. Pemetrexed is an antifolate agent that is currently used as the second line chemotherapy drug in the treatment of advanced NSCLC patients with a response rate of 20–40%. The search for any combination therapy to improve the efficacy of pemetrexed is required. The existence of cancer stem cells (CSCs) is considered as the main reason for drug resistance of cancers. In this study, we first found that pemetrexed-resistant NSCLC cells derived from A549 cells displayed higher CSC activity in comparison to the parental cells. The expression of CSC related proteins, such as BMI1 or CD44, and the epithelial–mesenchymal transition (EMT) signature was elevated in pemetrexed-resistant NSCLC cells. We next discovered that the overexpression of BMI1 in A549 cells caused the pemetrexed resistance and inhibition of BMI1 by a small molecule inhibitor, PTC-209, or transducing of BMI1-specific shRNAs suppressed cell growth and the expression of thymidylate synthase (TS) in pemetrexed-resistant A549 cells. We further identified that BMI1 positively regulated SP1 expression and treatment of mithramycin A, a SP1 inhibitor, inhibited cell proliferation, as well as TS expression, of pemetrexed-resistant A549 cells. Furthermore, overexpression of BMI1 in A549 cells also caused the activation of EMT in and the enhancement of CSC activity. Finally, we demonstrated that pretreatment of PTC-209 in mice bearing pemetrexed-resistant A549 tumors sensitized them to pemetrexed treatment and the expression of Ki-67, BMI1, and SP1 expression in tumor tissues was observed to be reduced. In conclusion, BMI1 expression level mediates pemetrexed sensitivity of NSCLC cells and the inhibition of BMI1 will be an effective strategy in NSCLC patients when pemetrexed resistance has developed.

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Section: Resultsmentioning

confidence: 99%

BMI1-Mediated Pemetrexed Resistance in Non-Small Cell Lung Cancer Cells Is Associated with Increased SP1 Activation and Cancer Stemness

Shen

Chien

Chen

et al. 2020

Cancers

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“…It has been evident that CD44 as a surface biomarker of cancer stem cells (CSCs) and a vital regulatory factor of epithelial-mesenchymal transition (EMT) program is involved in the regulation of tumor initiation and development [6,[15][16][17]. Aberrant expression of CD44 and dysregulation of CD44 contribute to tumor formation of multiple cancer entities, including lung cancer [18], hepatocellular carcinoma [19], ovarian cancer [20], glioma [21], papillary thyroid carcinoma [22], head and neck squamous cell carcinoma (HNSCC) [23], astrocytic gliomas [24] and oral squamous cell carcinoma (OSCC) [25]. In hepatocellular carcinoma cells (HuH7) which originally express CD44s rather than CD44v, silence of CD44 gene impaired the potential of spheroid formation and enhanced sensitivity to sorafenib and 5-fluorouracil (5-FU), accompanied by remarkable downregulation of CSC-related genes including CD133 and EpCAM [19].…”

Section: Open Accessmentioning

confidence: 99%

“…The 3′ untranslated region of CD44, acting as a competing endogenous RNA to microRNA-34a, boosts the sensitivity of liver CSCs to natural kill cells-mediated cytotoxicity via regulating UL16 binding protein 2 [26]. In addition, CD44 also exerts significant effects on caner invasion and metastasis of various tumor types [27], such as lung adenocarcinoma [18], breast cancer [28][29][30], neuroblastoma [31], gastric cancer [32], esophageal squamous cell carcinoma (ESCC) [33], colorectal cancer [34][35][36][37], prostate cancer [38], nasopharyngeal carcinoma [39], endometrial cancer [40], clear cell renal cell (RCC) carcinoma [41], pancreatic cancer [42], meningioma [43] and ovarian cancer [44]. As has been reported, the intracellular domain (ICD) of CD44 interacting with RUNX2 to form a co-transcription factor drives the migration of prostate cancer cell line PC3 through upregulating the levels of metastasis-related genes, such as matrix metalloproteinase 9 (MMP9) and osteopontin [38].…”

Section: Open Accessmentioning

confidence: 99%

“…CD44, which is encoded by CD44 gene on the short arm of chromosome 11 in human, is a type of complex cell-surface glycoprotein [6]. The CD44 gene is composed of 19 exons in human, among which the first five exons (exons 1-5) and the last five exons (exons [16][17][18][19][20] constantly encode CD44s which is the most common and the smallest CD44 protein with a molecule weight of 85-95 kDa [50]. The exons 1-5 and exons 16-20, regarded as stable exons, encode N-terminal containing HA-binding region and C-terminal domain of CD44 protein, respectively [51].…”

Section: The Structure and Function Of Cd44mentioning

confidence: 99%

“…CD44 plays essential roles in cancer progression of multiple tumor types, including breast cancer [110], lung adenocarcinoma [18], ovarian cancer [20], and glioblastoma [111]. Invasion from in situ to adjacent tissues of tumor cells occurs before metastasis and contributes to cancer development [110].…”

Section: Cd44 and Tumor Developmentmentioning

confidence: 99%

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CD44 as a tumor biomarker and therapeutic target

et al. 2020

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CD44, a complex transmembrane glycoprotein, exists in multiple molecular forms, including the standard isoform CD44s and CD44 variant isoforms. CD44 participates in multiple physiological processes, and aberrant expression and dysregulation of CD44 contribute to tumor initiation and progression. CD44 represents a common biomarker of cancer stem cells, and promotes epithelial-mesenchymal transition. CD44 is involved in the regulation of diverse vital signaling pathways that modulate cancer proliferation, invasion, metastasis and therapy-resistance, and it is also modulated by a variety of molecules in cancer cells. In addition, CD44 can serve as an adverse prognostic marker among cancer population. The pleiotropic roles of CD44 in carcinoma potentially offering new molecular target for therapeutic intervention. Preclinical and clinical trials for evaluating the pharmacokinetics, efficacy and drug-related toxicity of CD44 monoclonal antibody have been carried out among tumors with CD44 expression. In this review, we focus on current data relevant to CD44, and outline CD44 structure, the regulation of CD44, functional properties of CD44 in carcinogenesis and cancer progression as well as the potential CD44-targeting therapy for cancer management.

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Systems biology approach to identify biomarkers and therapeutic targets for colorectal cancer

Sadat Kalaki,

Ahmadzadeh,

Najafi

et al. 2024

Biochemistry and Biophysics Reports

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The subpopulation of CD44-positive cells promoted tumorigenicity and metastatic ability in lung adenocarcinoma

Cited by 26 publications

References 28 publications

BMI1-Mediated Pemetrexed Resistance in Non-Small Cell Lung Cancer Cells Is Associated with Increased SP1 Activation and Cancer Stemness

BMI1-Mediated Pemetrexed Resistance in Non-Small Cell Lung Cancer Cells Is Associated with Increased SP1 Activation and Cancer Stemness

CD44 as a tumor biomarker and therapeutic target

Systems biology approach to identify biomarkers and therapeutic targets for colorectal cancer

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