Cell adhesion molecule CD44v10 promotes stem-like properties in triple-negative breast cancer cells via glucose transporter GLUT1-mediated glycolysis

Abstract

Cell adhesion molecule CD44v8-10 is associated with tumor ste0mness and malignancy; however, whether CD44v10 alone confers these properties is unknown. Here, we demonstrated that CD44v10 promotes stemness and chemoresistance of triple-negative breast cancers (TNBCs) individually. Next, we identified that genes differentially expressed in response to ectopic expression of CD44v10 are mostly related to glycolysis. Further, we showed that CD44v10 upregulates glucose transporter 1 to facilitate glycolysis by activating the MAPK/ERK and PI3K/AKT signaling pathways. This glycolytic reprogramming induced by CD44v10 contributes to the stem-like properties of TNBC cells and confers resistance to paclitaxel treatment. Notably, we determined that the knockdown of glucose transporter 1 could attenuate the enhanced effects of CD44v10 on glycolysis, stemness, and paclitaxel resistance. Collectively, our findings provide novel insights into the function of CD44v10 in TNBCs and suggest that targeting CD44v10 may contribute to future clinical therapy. Cell adhesion molecule CD44v8-10 is associated with tumor ste0mness and malignancy; however, whether CD44v10 alone confers these properties is unknown. Here, we demonstrated that CD44v10 promotes stemness and chemoresistance of triple-negative breast cancers (TNBCs) individually. Next, we identified that genes differentially expressed in response to ectopic expression of CD44v10 are mostly related to glycolysis. Further, we showed that CD44v10 upregulates glucose transporter 1 to facilitate glycolysis by activating the MAPK/ERK and PI3K/AKT signaling pathways. This glycolytic reprogramming induced by CD44v10 contributes to the stem-like properties of TNBC cells and confers resistance to paclitaxel treatment. Notably, we determined that the knockdown of glucose transporter 1 could attenuate the enhanced effects of CD44v10 on glycolysis, stemness, and paclitaxel resistance. Collectively, our findings provide novel insights into the function of CD44v10 in TNBCs and suggest that targeting CD44v10 may contribute to future clinical therapy. Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancers (BrCas), in which the higher frequency of cancer stem cells (CSCs) correlates with a dismal prognosis. Despite the current standard cure modalities, such as surgery, chemotherapy, and radiotherapy, most TNBC patients inevitably suffer from drug resistance and tumor recurrence. Therefore, a better understanding of the molecular basis for TNBC progression is urgently needed to discover new and more effective therapeutic targets for patients. CD44 is a major adhesion molecule and has been implicated in various biological behaviors, such as cell differentiation and cell motility, as well as tumor growth and metastasis (1Zöller M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule?.Nat. Rev. Cancer. 2011; 11: 254-267Crossref PubMed Scopus (842) Google Scholar, 2Ponta H. Sherman L. Herrlich P.A. CD44: from adhesion molecules to signalling regulators.Nat. Rev. Mol. Cell Biol. 2003; 4: 33-45Crossref PubMed Scopus (1871) Google Scholar). The human CD44 gene consists of 19 exons and undergoes extensive alternative splicing that generates two families of isoforms, the standard CD44 form (CD44s) and the variant CD44 isoforms (CD44v). In contrast to the ubiquitous expression of CD44s, CD44v, which contains one or more variant exons, seems to be restricted to subpopulations endowed with stem cell potential and tumor development. Among CD44v, CD44v10-containing isoforms encompass a group of isoforms, such as CD44v8-10, CD44v3-10, and CD44v2-10, which have been identified as the most abundant variants (2Ponta H. Sherman L. Herrlich P.A. CD44: from adhesion molecules to signalling regulators.Nat. Rev. Mol. Cell Biol. 2003; 4: 33-45Crossref PubMed Scopus (1871) Google Scholar, 3Zhang H. Brown R.L. Wei Y. Zhao P. Liu S. Liu X. et al.CD44 splice isoform switching determines breast cancer stem cell state.Genes Dev. 2019; 33: 166-179Crossref PubMed Scopus (96) Google Scholar). It has also been reported that CD44v10-containing isoforms are involved in regulating metastasis, stemness, and chemoresistance of several cancers (4Bourguignon L.Y. Gunja-Smith Z. Iida N. Zhu H.B. Young L.J. Muller W.J. et al.CD44v(3,8-10) is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase (MMP-9) association in metastatic breast cancer cells.J. Cell Physiol. 1998; 176: 206-215Crossref PubMed Scopus (245) Google Scholar, 5Lau W.M. Teng E. Chong H.S. Lopez K.A. Tay A.Y. Salto-Tellez M. et al.CD44v8-10 is a cancer-specific marker for gastric cancer stem cells.Cancer Res. 2014; 74: 2630-2641Crossref PubMed Scopus (151) Google Scholar, 6Hagiwara M. Kikuchi E. Tanaka N. Kosaka T. Mikami S. Saya H. et al.Variant isoforms of CD44 involves acquisition of chemoresistance to cisplatin and has potential as a novel indicator for identifying a cisplatin-resistant population in urothelial cancer.BMC Cancer. 2018; 18: 113Crossref PubMed Scopus (31) Google Scholar). Blockade of CD44v10 could downregulate the expressions of all isoforms containing exon-v10 and consequently delay tumor growth and metastasis (7Guo Q. Liu Y. He Y. Du Y. Zhang G. Yang C. et al.CD44 activation state regulated by the CD44v10 isoform determines breast cancer proliferation.Oncol. Rep. 2021; 45: 7Crossref PubMed Scopus (2) Google Scholar, 8Iida J. Clancy R. Dorchak J. Somiari R.I. Somiari S. Cutler M.L. et al.DNA aptamers against exon v10 of CD44 inhibit breast cancer cell migration.PLoS One. 2014; 9e88712Crossref Scopus (33) Google Scholar, 9Megaptche A.P. Erb U. Büchler M.W. Zöller M. CD44v10, osteopontin and lymphoma growth retardation by a CD44v10-specific antibody.Immunol. Cell Biol. 2014; 92: 709-720Crossref PubMed Scopus (12) Google Scholar). Therefore, targeting CD44v10-positive cancer cells arises as a promising cancer therapy option. However, the question of whether it is CD44v10 alone or CD44v10 cooperates with its related isoforms together that influences cancer behaviors remains unanswered. In this study, we first demonstrated that CD44v10 is preferentially expressed in TNBC patients and correlates with tumor progression. Next, we generated a breast cancer cell line transfected with CD44v10 cDNA and identified that glycolysis-related genes were significantly upregulated in response to CD44v10 overexpression. As reported before, abnormal glycolysis metabolism is usually adopted by CSCs, such as glucose uptake, glycolytic enzyme expression, and lactate production which are elevated in CSCs as compared with their differentiated offspring (10Sancho P. Barneda D. Heeschen C. Hallmarks of cancer stem cell metabolism.Br. J. Cancer. 2016; 114: 1305-1312Crossref PubMed Scopus (310) Google Scholar, 11Dong C. Yuan T. Wu Y. Wang Y. Fan T.W. Miriyala S. et al.Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer.Cancer Cell. 2013; 23: 316-331Abstract Full Text Full Text PDF PubMed Scopus (565) Google Scholar, 12Feng W. Gentles A. Nair R.V. Huang M. Lin Y. Lee C.Y. et al.Targeting unique metabolic properties of breast tumor initiating cells.Stem Cells. 2014; 32: 1734-1745Crossref PubMed Scopus (91) Google Scholar, 13Liu P.P. Liao J. Tang Z.J. Wu W.J. Yang J. Zeng Z.L. et al.Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway.Cell Death Differ. 2014; 21: 124-135Crossref PubMed Scopus (159) Google Scholar). Moreover, certain CD44v isoforms, such as CD44v3, CD44v6, and CD44v8-10, could act as CSCs markers and play critical roles in promoting the properties of CSCs (5Lau W.M. Teng E. Chong H.S. Lopez K.A. Tay A.Y. Salto-Tellez M. et al.CD44v8-10 is a cancer-specific marker for gastric cancer stem cells.Cancer Res. 2014; 74: 2630-2641Crossref PubMed Scopus (151) Google Scholar, 14Bourguignon L.Y. Wong G. Earle C. Chen L. Hyaluronan-CD44v3 interaction with Oct4-Sox2-Nanog promotes miR-302 expression leading to self-renewal, clonal formation, and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma.J. Biol. Chem. 2012; 287: 32800-32824Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 15Todaro M. Gaggianesi M. Catalano V. Benfante A. Iovino F. Biffoni M. et al.CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis.Cell Stem Cell. 2014; 14: 342-356Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar). These findings raise the possibility that CD44v10 may be involved in regulating the stem-like features. We next performed transcriptomic analysis and determined that CD44v10 enhances glycolysis through glucose transporter 1 (GLUT1) upregulation, which could maintain TNBC cells stem-like properties and confer paclitaxel (PTX) resistance. Notably, silencing of GLUT1 could markedly suppress the enhanced effects of CD44v10 on glycolysis and stem-like properties. Taken together, our findings suggested that CD44v10 could promote BrCas stemness individually without cooperating with other CD44 variants. The underneath mechanism of CD44v10-GLUT1 may point to CD44v10 as a specific therapeutic target to the clinic in TNBC. To investigate the potential role of CD44v10 in BrCas, we first analyzed its expression in a cohort of 25 paired BrCas tissues. The of showed that CD44v10 were elevated in cancer Next, to the CD44v10 and BrCas we CD44v10 expressions molecular by which contains of BrCas, of BrCas with and of that CD44v10 expression significantly elevated in TNBCs compared with that in and BrCas an role of CD44v10 in the of were by several human cell that CD44v10 expression higher in TNBC cell and human breast cells we analyzed the CD44v10 and in cohort 1 and cohort patients. We an of CD44v10 expression with tumor and however, with CD44v10 expression higher and more Moreover, were in an containing human BrCas to the CD44v10 and The that BrCas patients with higher expression of CD44v10 showed Collectively, these suggested that CD44v10 is preferentially expressed in TNBC patients and may play a role in the of human of CD44v10 overexpression. CD44v10 expression of human breast cells and TNBC cells and were analyzed by as the CD44 expression of TNBC cells CD44v10 were analyzed by of CD44v10 by of and CD44v10 the and the the and genes are in and gene analysis of upregulated differentially expressed genes in of biological gene analysis of the of glycolysis and glycolysis gene in CD44v10 cells compared with triple-negative breast of CD44v10 expression with the of breast cancer expression a in a new The a showed that expressions of all isoforms containing exon-v10 were significantly in cells CD44v10 (7Guo Q. Liu Y. He Y. Du Y. Zhang G. Yang C. et al.CD44 activation state regulated by the CD44v10 isoform determines breast cancer proliferation.Oncol. Rep. 2021; 45: 7Crossref PubMed Scopus (2) Google Scholar). In the study, were by other TNBC cell and To the roles of CD44v10 in TNBC we a cell line by of CD44v10 cDNA into cells which contains CD44v10 The in cells with or CD44v10 were by expression analysis and genes significantly upregulated and in CD44v10 cells compared with that genes upregulated in CD44v10 cells were significantly for related to glycolysis, and To this we gene analysis and a of glycolysis gene in CD44v10 group compared with cells Taken together, our suggested that CD44v10 may be involved in glycolysis. To the we next the in glycolytic metabolism by CD44v10 In to we also CD44v10 in which a of CD44v10 that glycolytic is by glucose and lactate with R. D. J. W. J. Wang J. et promotes breast cancer stemness glucose 2018; PubMed Scopus Google we whether of CD44v10 expression of and that ectopic expression of CD44v10 glucose and lactate as well as the knockdown of CD44v10 such effects These findings suggested that CD44v10 could promote the glycolytic of TNBC To into the mechanism by which CD44v10 TNBC glycolytic the gene expression of glycolytic in the glucose metabolic were compared and CD44v10 As most of the glycolysis-related genes were upregulated in CD44v10 cells We these gene expression by and and that were upregulated CD44v10 and Next, the expressions of the genes were and the showed that the of glucose uptake, significantly in CD44v10 of and were CD44v10 ectopic expression and These suggested that GLUT1 may be for the glycolysis. To the of GLUT1 in glycolysis, we next whether the knockdown of GLUT1 the glycolytic by CD44v10 overexpression. The CD44v10 cells were transfected with or GLUT1 As in the of GLUT1 the of glucose and lactate production induced by CD44v10 overexpression. also on which showed that the knockdown of GLUT1 the by CD44v10 Further, we the mechanism by which CD44v10 GLUT1 As we reported that CD44v10 could MAPK/ERK and PI3K/AKT signaling (7Guo Q. Liu Y. He Y. Du Y. Zhang G. Yang C. et al.CD44 activation state regulated by the CD44v10 isoform determines breast cancer proliferation.Oncol. Rep. 2021; 45: 7Crossref PubMed Scopus (2) Google and have that such signaling could the GLUT1 expression H. C. Zhang J. Zhao J. T. et of GLUT1 from by the of in stem J. PubMed Scopus Google Scholar, C. Chen Q. Y. Y. Wang X. X. et promotes glycolysis and GLUT1 regulation in J. PubMed Scopus Google we next whether MAPK/ERK and PI3K/AKT are in the of As the of the signaling could the GLUT1 Collectively, the suggested that CD44v10 may GLUT1 activating MAPK/ERK and PI3K/AKT signaling in glycolysis. reprogramming in cancer cells has been reported to the of CSCs properties W. Gentles A. Nair R.V. Huang M. Lin Y. Lee C.Y. et al.Targeting unique metabolic properties of breast tumor initiating cells.Stem Cells. 2014; 32: 1734-1745Crossref PubMed Scopus (91) Google Scholar). it is that CD44v has been identified as one of the markers of CSCs in which to investigate whether glycolysis could contribute to the stemness properties of TNBC we that CD44v10 the of compared to the cells in CD44v10 knockdown the As the knockdown of CD44v10 could the expressions of all CD44v10-containing isoforms, we next performed a by CD44v10 in cells to the role of CD44v10 in TNBC The showed that the of CD44v10 could the of by CD44v10 knockdown In and are and of stem cells and CSCs L. P. Zhao G. J. W. Zhang J. et al.Targeting cancer stem cell for cancer PubMed Scopus Google Scholar). We next the effects of CD44v10 on the expressions of these and that their expressions were upregulated in CD44v10 cells in the group are to breast C. E. F. J. Brown M. et is a marker of and human stem cells and a of clinical Stem Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). In line with these the of cells from to in CD44v10 compared with it from to in compared with cells To the function of CD44v10 on stemness, we analyzed the expression of CD44v10 in TNBC cell as or in The showed that and of CD44v10 were elevated in cells compared to their cells and To the of GLUT1 in stemness, we whether the knockdown of GLUT1 could attenuate the enhanced stemness by CD44v10 overexpression. As in and GLUT1 knockdown the of and stemness gene expression induced by elevated expression of CD44v10 in Taken together, these that CD44v10 confers TNBC stem by GLUT1 CSCs are for tumor resistance to is a for TNBC patients. In of the role of CD44v10 in CSCs we to investigate whether the CD44v10 isoform is associated with to showed that the expression of CD44v10 with genes and in a in and cell In the effects of of on cells and their cells were of by The that the of CD44v10 in cells in resistance to and its knockdown in cells enhanced drug to growth To the role of CD44v10 in regulating we performed and that the of CD44v10 could attenuate the by CD44v10 knockdown were also in These findings that CD44v10 is associated with tumor resistance to To the of glycolysis in we GLUT1 in CD44v10 cells and that the knockdown of GLUT1 could the by CD44v10 CD44v10-containing isoforms have been for their in tumor metastasis, and However, is whether CD44v10 role in cancer progression compared to such as and In this study, we demonstrated that CD44v10 promotes stem-like properties and of TNBC cells in we reported a novel mechanism of CD44v10 on BrCas stemness through glucose which is by glycolysis. expression of CD44v10 has been in several cancers and correlates with a N. M. Y. H. S. of CD44 isoform v10 expression and its in cell PubMed Google Scholar, C. G. of CD44 splice variant v10 in is associated with and of 1998; PubMed Scopus Google Scholar, Wong G. W. L.Y. CD44 variant isoforms in head and neck squamous cell PubMed Scopus Google has the role of CD44v10 in we the clinical of CD44v10 in breast cancer patients and that CD44v10 preferentially expressed in TNBC patients compared with or Notably, patients with CD44v10 expression higher and as well as a potential role of CD44v10 in BrCas progression. have that CD44v10-containing isoforms, such as CD44v8-10, and to are related to cancers in (4Bourguignon L.Y. Gunja-Smith Z. Iida N. Zhu H.B. Young L.J. Muller W.J. et al.CD44v(3,8-10) is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase (MMP-9) association in metastatic breast cancer cells.J. Cell Physiol. 1998; 176: 206-215Crossref PubMed Scopus (245) Google Scholar, 5Lau W.M. Teng E. Chong H.S. Lopez K.A. Tay A.Y. Salto-Tellez M. et al.CD44v8-10 is a cancer-specific marker for gastric cancer stem cells.Cancer Res. 2014; 74: 2630-2641Crossref PubMed Scopus (151) Google Scholar, J. H. C. A. M. et cell CD44v isoforms promote cancer in of 2014; 33: PubMed Scopus Google Scholar). However, the function of CD44v10 alone unknown. the that the knockdown of exon-v10 could downregulate all expressions of CD44v10-containing isoforms (7Guo Q. Liu Y. He Y. Du Y. Zhang G. Yang C. et al.CD44 activation state regulated by the CD44v10 isoform determines breast cancer proliferation.Oncol. Rep. 2021; 45: 7Crossref PubMed Scopus (2) Google we performed transcriptomic analysis by a CD44v10 cell line of CD44v10 knockdown to for on CD44v10 in regulating BrCas progression. We that the differentially expressed genes induced by ectopic expression of CD44v10 were mostly associated with glycolytic We that CD44v10 could promote glycolytic glucose and lactate production with CD44v10 such These findings were with that CD44 is involved in the regulation of the glycolytic in cancer cells M. S. M. T. T. et of glucose metabolism by CD44 contributes to and drug resistance in cancer cells.Cancer Res. 2012; PubMed Scopus Google Scholar, W. A. Y. J. D. et role of CD44 in glucose metabolism in cell Res. 2016; 14: PubMed Scopus Google Scholar). To investigate the mechanism of glycolysis, we on glycolysis-related transcriptomic analysis of TNBC we identified that GLUT1 the most upregulated gene in CD44v10 As before, GLUT1 is the transporter for glucose and has been reported to be significantly elevated in TNBCs S. A. Q. T. et expression correlates with basal-like breast 2011; 4: PubMed Scopus Google Scholar). GLUT1 with CD44v10 for the findings that GLUT1 could attenuate glycolysis in TNBC However, it be that GLUT1 the glycolytic we that CD44v10 may facilitate glycolysis through of GLUT1 expression with other genes which In with our a that CD44 could suppress GLUT1 expression M. S. M. T. T. et of glucose metabolism by CD44 contributes to and drug resistance in cancer cells.Cancer Res. 2012; PubMed Scopus Google in which the mechanism has been reported that CD44v10 could MAPK/ERK and PI3K/AKT signaling (7Guo Q. Liu Y. He Y. Du Y. Zhang G. Yang C. et al.CD44 activation state regulated by the CD44v10 isoform determines breast cancer proliferation.Oncol. Rep. 2021; 45: 7Crossref PubMed Scopus (2) Google Scholar). demonstrated that the of GLUT1 associated with the signaling H. C. Zhang J. Zhao J. T. et of GLUT1 from by the of in stem J. PubMed Scopus Google Scholar, M.L. Huang T. H. et growth upregulates glucose transporter 1 and glycolysis through and in J. 2021; PubMed Scopus Google Scholar). Therefore, we whether CD44v10 could GLUT1 by MAPK/ERK and PI3K/AKT pathways. with our the of the significantly GLUT1 expression, that CD44v10 may GLUT1 through the activation of MAPK/ERK and PI3K/AKT signaling pathways. It has been well that metabolic reprogramming is one of the of cancer D. Hallmarks of the next 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). suggested that CSCs may have higher glycolytic compared with the of the cancer cells W. Gentles A. Nair R.V. Huang M. Lin Y. Lee C.Y. et al.Targeting unique metabolic properties of breast tumor initiating cells.Stem Cells. 2014; 32: 1734-1745Crossref PubMed Scopus (91) Google Scholar, 13Liu P.P. Liao J. Tang Z.J. Wu W.J. Yang J. Zeng Z.L. et al.Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway.Cell Death Differ. 2014; 21: 124-135Crossref PubMed Scopus (159) Google Scholar). As CD44v8-10 and could facilitate in gastric cancer and cancer (5Lau W.M. Teng E. Chong H.S. Lopez K.A. Tay A.Y. Salto-Tellez M. et al.CD44v8-10 is a cancer-specific marker for gastric cancer stem cells.Cancer Res. 2014; 74: 2630-2641Crossref PubMed Scopus (151) Google Scholar, J. H. C. A. M. et cell CD44v isoforms promote cancer in of 2014; 33: PubMed Scopus Google we whether CD44v10 function a role in the regulation of TNBC stemness properties that elevated CD44v10 in of TNBC cells also to a stem These findings suggested that CD44v10 alone may confer stemness properties and act as a marker of CSCs in TNBC. Notably, we also demonstrated that the of GLUT1 glycolytic and the enhanced stemness induced by CD44v10 upregulation, a novel mechanism by which CD44 variants confer stem-like properties of cancer In of these CD44v10 may individually promote stem properties of TNBC cells through glycolysis. of has that cancer cells CSCs chemoresistance T. T. M. T. H. et al.CD44 variant in cancer cells by the of and promotes tumor Cell. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar, T. T. T. M. et splicing of CD44 by enhances of metastatic cancer 2012; PubMed Scopus Google Scholar). the potential role of CD44v10 in CSCs we next whether CD44v10 could play a role in We performed drug in and that TNBC cells with expressed higher of CD44v10 with genes in a the of CD44v10 alone could inhibit the to cell of CD44v10 this the of CD44v10 in the regulation of In with our a that CD44v8-10 to cisplatin in urothelial cancer M. Kikuchi E. Tanaka N. Kosaka T. Mikami S. Saya H. et al.Variant isoforms of CD44 involves acquisition of chemoresistance to cisplatin and has potential as a novel indicator for identifying a cisplatin-resistant population in urothelial cancer.BMC Cancer. 2018; 18: 113Crossref PubMed Scopus (31) Google Scholar). other CD44 variant exons, such as and have also been to confer resistance to cancer cells through the regulation of S. C. C. from isoforms influences response and of gastric cancer PubMed Scopus Google Scholar, S. S. J. J. E. et stem as in 2019; PubMed Scopus Google Scholar, T. E. R. Y. Y. et of CD44 variant chemoresistance of gastric cancer by Cancer. 2021; PubMed Scopus Google Scholar). In of the of our raise the possibility that CD44v10 the of TNBC cells to against we that the of by CD44v10 could be by GLUT1 To this we a that targeting CD44v10 may the glucose metabolism of CSCs and the of TNBC cells to which In our the roles of CD44v10 alone in promoting stemness properties and regulating through glycolysis, that CD44v10 may be a therapeutic target to TNBC therapy. cell and were from the Cell of the of the of human cell have been the cells were in cells were in and and cells were in the were with and with a of to the of and cell were a of in with In all cells were to for the were performed with The and were from The standard and were to the of human BrCas were from To investigate the expression of CD44v10 in human BrCas, a 25 paired breast and by To the of CD44v10 in of BrCas, cohort that of breast tumor of BrCas, of BrCas with and of and a containing patients to the CD44v10 and for CD44v10 performed as reported C. M. Liu Y. He Y. Du Y. Zhang G. et of cells by CD44 switching to and in breast 2019; PubMed Scopus Google Scholar). these were as and of as well as a CD44v10 and the were with the were with a for 1 by the were with a and with The of CD44v10 were analyzed from cells a with the with were performed by to the of gene were against that of The expression of genes by the The for are in for the determined by a were by and The were with in for 1 and with CD44v10 GLUT1 Cell and the were the were the enhanced and were on an The targeting human CD44v10 expression were and by and performed with to the for CD44v10 GLUT1 and the CD44v10 into the for CD44v10 by and into the were with to the and with for to or The knockdown and were by to the The were an the of gene and the of gene were by expression analysis performed the We a with as the for significantly and analysis of differentially expressed genes were performed on the analysis performed to whether a of genes CD44v10 and and lactate of the were by a and to the of were determined by to the were into a of 1 cells well and in with human growth and human growth for were in and the The of in an The to one cells were in containing the and for As a an of cell with a specific cells were analyzed on the and analysis performed The of cells to by were in a of cells well and with various or of the cells were for and to well to the for an a of BrCas cells by cells a of in a and of of cells were with with for by with for the were and the of by the analysis performed are as the group standard analysis performed an for and a analysis of for in were by the The to be all were with The that the findings of this are in the of this This contains The of with the of the Q. 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