**5.9 Glioblastoma**

**5.8 Bladder cancer**

*Current Cancer Treatment*

also SOX4 [144].

**Figure 12.**

**Table 16.**

**Table 17.**

**18**

*miRNA and bladder cancer.*

*MicroRNAs activating the bladder cancer.*

*MicroRNAs suppressing the bladder cancer.*

In males, bladder cancer is an important malignancy present in two forms that

(**Figure 12**) [141, 142]. The known targets of miR-129 are the genes involved in the regulation of transcription and processing of miRNA that are TAMTA1 and EIF2CA [143]. The mir-129's pathway of death effectors leads to the tumor as its target is

According to one study, miR-19a is frequently upregulated in the bladder cancer. The expression of miR-19a is related to PTEN expression (**Table 16**). PTEN is a tumor suppressor gene. When miR-19a is overexpressed, it causes the downregulation of PTEN and increases the cell level of phosphatidylinositol-3,4,5 trisphosphate in AKT/PKB pathway. When growth factors are released, then the

Zhang studied that miR-125b is downregulated in bladder cancer. The expression of miR-135b causes the inhibition of formation of colony and development of cancer via suppression of E2F3 which is overexpressed in bladder cancer [74]. In another study angiogenesis in the bladder cancer is suppressed by miR-34a (**Table 17**). The target of miR-34a is CD44 and causes the suppression of CD44 when upregulated which results in the regulation of transcription of the various

**Sr. no. MicroRNAs Potential targets Function Ref.** miR-129 TAMTA1 and EIF2CA Regulation of transcription [143] miR-21 TPM1 and PTEN Growth of tumor cell [141] miR-19a PTEN Increase in the cell growth [145]

**Sr. no. MicroRNAs Potential targets Function Ref.**

development of cancer

migration, tube formation, and angiogenesis

[74]

[146]

1 miR-125b E2F3 Inhibition of formation of colony and

2 miR-34a CD44 Inhibition of invasion, metastasis,

are muscle invasive and non-muscle invasive (benign) [139]. There are two microRNAs associated with bladder cancer. They are miR-21 and miR-129 [140]. In the bladder cancer, miR-129 and miR-21 both are upregulated. The direct

target of miR-21 is the tumor suppressor genes that are TPM1 and PTEN

AKT pathway is initiated and cell growth is increased [145].

Glioblastoma is the tumor of astrocytes, star-shaped cells that form the supportive tissues (glue-like) of the brain. This is readily metastasizing tumor because it is surrounded by large blood vessels. Glioblastoma is a complex and heterogeneous tumor that comprises on neoplastic cells, endothelial cells, stemlike cells, neural precursor cells, microglia, reactive extracellular components, and peripheral immune cells [147].

The biomarker in glioblastoma is miR-21 that is upregulated in this cancer (**Figure 13**). It mediates its effect in two ways: acting at the translational level and acting at the transcription level. It binds the 3<sup>0</sup> UTR region of the target gene (for apoptosis) [148] and causes the inhibition of transcription of apoptotic genes by decreasing the stability. It also resists the caspases 3 and 7 that are important apoptotic agents so apoptosis does not occur [149].

Upregulation of miR-221 and miR-222 was in glioma cells. These two miRNAs present as a cluster on Xp11.3 and have the same target. Functional studies revealed that there is an association of these two miRNAs with the progression of the cell cycle. Their direct target is cyclin-dependent kinase 1B/p27. The overexpression of these miRNAs cause the activation of quiescent glioblastoma cells and the progression of these cells from G1 phase to S phase of the cell cycle. miR-221/miR-222 also targets the p57 and p27 (inhibitors of cell-dependent kinase) to prevent the quiescence at G1 phase and cause their entry to S phase of the cell cycle. The miR-221/miR-222 also targets the PUMA, a proapoptotic protein, to prevent the apoptosis (**Table 18**) [150].

Another biomarker miR-128 is found to be downregulated in glioblastoma. The expression of miR-128 causes the regulation of proliferation of glioblastoma multiform (GBM) cells via targeting the PDGFR-α and EGFR, the oncogenic kinases

**Figure 13.** *miRNA and glioblastoma.*


**Table 18.** *MicroRNAs activating the glioblastoma.*

(receptor tyrosine kinases) (**Table 19**). It suppresses the GBM by enhancing the differentiation of neuronal cells. It also targets the signaling molecules in the PI3-kinase/AKT pathway which causes the tumor cell proliferation [147].

is a tumor suppressor gene. When these miRNAs are downregulated, then the expression of p53 is reduced or inhibited, and expression of BCL-2 is increased

In one study, miR-17/miR-92 cluster is overexpressed in the B cell lymphocytic leukemia (**Table 21**). The direct target of this cluster is PTEN and Bim. The PTEN is a tumor suppressor gene, and Bim is proapoptotic protein. Overexpression of this cluster causes prevention of apoptosis and progression of tumor [157]. In other study, miR-155 is overexpressed in the B cell lymphocytic leukemia [159]. The potential target for miR-155 is SHIP1. Expression of miR-155 causes the alteration of BCR response in signaling pathway via the modulation of SHIP1 expression in chronic lymphocytic leukemia. Scr homology-2 domain comprising the inositol 5-phosphatase is encoded by SHIP1. This phosphatase causes the inhi-

Pancreatic tumor is most of the time identified at the last stages when therapy does not save life. Li et al. characterize the pancreatic cancer stem cells (PCSCs) for

In one study, there is overexpression of miR-1290 in pancreatic cancer. The direct target of miR-1290 is FoxA1 which has an effect on the transition of epithelial mesenchyma. The overexpression of miR-1290 results in the growth of cell and

In another study there is overexpression of miR-194 in pancreatic cancer. The target of miR-194 is DACH1 and results in the formation of the colony, the proliferation of cell, and migration (**Table 22**), so miR-194 causes the progression

The growth and differentiation of the cell are regulated by LIN28, a protein that binds to the RNA [162]. The protein that is encoded by LIN28 is 25 kDa and has two binding sites for RNA: cold shock domain (CSD) and a pair of zinc fingers. In pancreatic cancer, the expression of LIN28 is increased which in turn suppresses the biosynthesis of family let-7 of microRNA (**Figure 15**). This family targets the genes involved in the growth and differentiation regulation [163]. This LIN28 causes the inhibition by binging to the loop present at the terminal region of let-7 family, so

**Sr. no. MicroRNAs Potential targets Function Ref.** 1 miR-19a PTEN Cause the tumor [155]

**Sr. no. MicroRNAs Potential targets Function Ref.** 1 miR-1290 FoxA1 Cell growth and invasion [94] 2 miR-194 DACH1 Progression of tumor [161]

progression of tumor

surface immunoglobulin

[157]

[158]

2 miR-17/miR-92 PTEN and Bim Prevention of apoptosis and

*MicroRNAs activating the B cell lymphocytic leukemia.*

*MicroRNAs activating the pancreatic cancer.*

3 miR-155 SHIP1 Inhibition of BCR signaling and

which prevent the apoptosis and cell survival is increased [156].

*MicroRNA: A Signature for Cancer Diagnostics DOI: http://dx.doi.org/10.5772/intechopen.90063*

bition of BCR signaling and surface immunoglobulin [158].

**5.11 Pancreatic cancer**

the very first time [160].

invasion [94].

**Table 21.**

**Table 22.**

**21**

of the tumor [161].

In other study miR-7 is downregulated in glioblastoma. Its target is EGFR and causes the inhibition of AKT pathways and EGFR and results in the reduction of cell viability of GBM via direct binding to mRNA of EGFR or via targeting to IRS1 and IRS2 (insulin receptor substrate). The major regulators EGFR and IRS are at upstream site of AKT pathway [151].

#### **5.10 B cell chronic lymphocytic leukemia**

This is the cancer of B lymphocytes (antibodies), and it is a prevalent form of leukemia in the adult around western countries [152].

In B cell leukemia, the expression of three microRNAs is seen as cancer biomarker. These are miR-15a, miR-16-1, and miR-19a (**Figure 14**). Two microRNAs are present at 13q14.3 chromosomal location; these are miR-15a and 16-1 [153]. The expression of these two is decreased in this leukemia, whereas the expression of miR-19a is increased [152]. The region encoding for miR-15a and miR-16-1 was deleted. This leads to the presence of the genes of IgVH that were mutated [154]. The potent target of miR-19a is PTEN, and there is down-expression of this PTEN gene; hence its protein is not properly synthesized because the promoter of the gene is hypermethylated [155].

The miR-16-1 and miR-15a (located on chromosome 13) are downregulated in B cell lymphocytic leukemia (**Table 20**). These miroRNAs target the p53 gene which


#### **Table 19.**

*MicroRNAs suppressing the glioblastoma.*

*miRNA and B cell lymphocytic leukemia.*


#### **Table 20.**

*MicroRNAs suppressing the B cell lymphocytic leukemia.*

#### *MicroRNA: A Signature for Cancer Diagnostics DOI: http://dx.doi.org/10.5772/intechopen.90063*

is a tumor suppressor gene. When these miRNAs are downregulated, then the expression of p53 is reduced or inhibited, and expression of BCL-2 is increased which prevent the apoptosis and cell survival is increased [156].

In one study, miR-17/miR-92 cluster is overexpressed in the B cell lymphocytic leukemia (**Table 21**). The direct target of this cluster is PTEN and Bim. The PTEN is a tumor suppressor gene, and Bim is proapoptotic protein. Overexpression of this cluster causes prevention of apoptosis and progression of tumor [157].

In other study, miR-155 is overexpressed in the B cell lymphocytic leukemia [159]. The potential target for miR-155 is SHIP1. Expression of miR-155 causes the alteration of BCR response in signaling pathway via the modulation of SHIP1 expression in chronic lymphocytic leukemia. Scr homology-2 domain comprising the inositol 5-phosphatase is encoded by SHIP1. This phosphatase causes the inhibition of BCR signaling and surface immunoglobulin [158].

#### **5.11 Pancreatic cancer**

(receptor tyrosine kinases) (**Table 19**). It suppresses the GBM by enhancing the differentiation of neuronal cells. It also targets the signaling molecules in the PI3-kinase/AKT pathway which causes the tumor cell proliferation [147].

upstream site of AKT pathway [151].

*Current Cancer Treatment*

is hypermethylated [155].

*MicroRNAs suppressing the glioblastoma.*

*miRNA and B cell lymphocytic leukemia.*

*MicroRNAs suppressing the B cell lymphocytic leukemia.*

**Table 19.**

**Figure 14.**

**Table 20.**

**20**

**5.10 B cell chronic lymphocytic leukemia**

leukemia in the adult around western countries [152].

In other study miR-7 is downregulated in glioblastoma. Its target is EGFR and causes the inhibition of AKT pathways and EGFR and results in the reduction of cell viability of GBM via direct binding to mRNA of EGFR or via targeting to IRS1 and IRS2 (insulin receptor substrate). The major regulators EGFR and IRS are at

This is the cancer of B lymphocytes (antibodies), and it is a prevalent form of

In B cell leukemia, the expression of three microRNAs is seen as cancer biomarker. These are miR-15a, miR-16-1, and miR-19a (**Figure 14**). Two microRNAs are present at 13q14.3 chromosomal location; these are miR-15a and 16-1 [153]. The expression of these two is decreased in this leukemia, whereas the expression of miR-19a is increased [152]. The region encoding for miR-15a and miR-16-1 was deleted. This leads to the presence of the genes of IgVH that were mutated [154]. The potent target of miR-19a is PTEN, and there is down-expression of this PTEN gene; hence its protein is not properly synthesized because the promoter of the gene

The miR-16-1 and miR-15a (located on chromosome 13) are downregulated in B cell lymphocytic leukemia (**Table 20**). These miroRNAs target the p53 gene which

**Sr. no. MicroRNAs Potential targets Function Ref.** 1 miR-128 PDGFR-α and EGFR Enhancing the differentiation of neuronal cells [147] 2 miR-7 EGFR Reduction of cell viability [151]

**Sr. no. MicroRNAs Potential targets Function Ref.**

survival is increased

survival is increased

[153]

[156]

1 miR-15a p53 Prevent the apoptosis and cell

2 miR-16-1 p53 Prevent the apoptosis and cell

Pancreatic tumor is most of the time identified at the last stages when therapy does not save life. Li et al. characterize the pancreatic cancer stem cells (PCSCs) for the very first time [160].

In one study, there is overexpression of miR-1290 in pancreatic cancer. The direct target of miR-1290 is FoxA1 which has an effect on the transition of epithelial mesenchyma. The overexpression of miR-1290 results in the growth of cell and invasion [94].

In another study there is overexpression of miR-194 in pancreatic cancer. The target of miR-194 is DACH1 and results in the formation of the colony, the proliferation of cell, and migration (**Table 22**), so miR-194 causes the progression of the tumor [161].

The growth and differentiation of the cell are regulated by LIN28, a protein that binds to the RNA [162]. The protein that is encoded by LIN28 is 25 kDa and has two binding sites for RNA: cold shock domain (CSD) and a pair of zinc fingers. In pancreatic cancer, the expression of LIN28 is increased which in turn suppresses the biosynthesis of family let-7 of microRNA (**Figure 15**). This family targets the genes involved in the growth and differentiation regulation [163]. This LIN28 causes the inhibition by binging to the loop present at the terminal region of let-7 family, so


#### **Table 21.**

*MicroRNAs activating the B cell lymphocytic leukemia.*


#### **Table 22.** *MicroRNAs activating the pancreatic cancer.*

**Figure 15.** *miRNA and pancreatic cancer.*

their processing is blocked [45, 46, 164]. This family is involved in the regulation of tumor by cyclin D1 (CCND1) inhibition [165, 166].

reduced (**Figure 16**). In acute myeloid leukemia, miR-29b results in the apoptosis when it directly targets the MCL (induced myeloid leukemia cell differentiation protein) [170]. So the expression of miR-29b is reduced in acute myeloid leukemia which leads to cancer progression as apoptosis has been decreased with reduced

2 miR-125b Bak1 Enhance proliferation and prevent apoptosis

In ovarian cancer, the biomarker that is used is miR-214 and it is upregulated in

and causes its hypermethylation. So this is inactivated. The direct target of PTEN is Akt protein kinase B and mediates its activation by the help of PI4K3B [171]. Akt causes the downstream effects such as activation of glycogen synthase. So when PTEN is inhibited, it activates the expression of Akt. This miR-214 resists the cisplatin-mediated cell death, so it is antiapoptotic in nature (**Figure 17**). Cisplatin is

In a study, there is overexpression of Hsa-miR-182 in ovarian cancer. The potential target of Hsa-miR-182 is forkhead box 3 (FOXO3) and forkhead box 1 (FOXO1) which promote the differentiation and inhibition of growth (acting as a tumor suppressor). These tumor suppressor genes are suppressed, and growth and

**Sr. no. MicroRNAs Potential targets Function** 1 miR-29b DNMT Apoptosis 2 miR-29b MCL protein Apoptosis

UTR region of phosphatase and tensin analog (PTEN) gene

Increase mutation rate in progenitor and

hematopoietic stem cells

expression of miR-29b (**Table 25**).

an important factor in mediating cell death [172].

**Sr. no. MicroRNAs Potential targets Function** 1 miR-204 MEIS1 and HOXA Tumorigenesis

3 miR-155 WEE1, hMLH1, hMLH6, and hMLH4

*MicroRNA: A Signature for Cancer Diagnostics DOI: http://dx.doi.org/10.5772/intechopen.90063*

*MicroRNAs activating the acute myeloid leukemia [169].*

proliferation of ovarian cell are increased (**Table 26**) [173].

**5.13 Ovarian cancer**

**Table 24.**

cancer. It binds to the 3<sup>0</sup>

**Figure 16.**

**Table 25.**

**23**

*miRNA and acute myeloid leukemia.*

*MicroRNAs suppressing the acute myeloid leukemia [170].*

In one study there is downregulation of miR-145 in pancreatic cancer. The decreased expression of miR-145 is due to activation of the K-ras gene. Expression of miR-145 causes the inhibition of expression of insulin growth factor-1 receptors (**Table 23**). Its expression causes the downregulation of genes related to cancer (SET, MCM2, SPTBN1). These genes cause growth and carcinogenesis of pancreatic cancer [161].

### **5.12 Acute myeloid leukemia**

In the myeloid leukemia, malignant blast cells are synthesized in comparison to mononuclear cells of healthy bone marrow [167]. In myeloid leukemia the hypermethylation of the DNA is involved in tumor suppression [168]. In one study, there is overexpression of miR-204 in acute myeloid leukemia. The target of miR-204 is MEIS1 and HOXA 10 genes which disturbs the differentiation of myeloid cells. Its overexpression causes tumorigenesis [169].

In another study, miR-125b (located on chromosome 1) is overexpressed in acute myeloid leukemia. The target of miR-125b is BCL2-antagonist/killer 1 (Bak1) which enhance the proliferation of AML cell and prevent the apoptosis [169].

In another study, miR-155 (located on chromosome 21) is overexpressed in the acute myeloid leukemia. This miR-155 is located in B cell integration cluster (BIC) gene. This BIC correlated to MYC to initiate lymphomas. Overexpression of miR-155 causes the inhibition of WEE1, a regulator of the cell cycle, and hMLH1, hMLH6, and hMLH4, the genes for mismatch repair (**Table 24**). The result of this inhibition is increased in mutation rate in progenitor and hematopoietic stem cells [169].

The known biomarker for the acute myeloid leukemia is miR-29b [167]. miR-29b causes the hypomethylation of the DNA. Sp1 transcriptional factor has the binding site for both miR-29b and DNMT1. In DNMT, it binds to its promoter and 30 UTR for miR-29b of Sp1 (specificity protein 1). Binding to the 3<sup>0</sup> UTR causes the reduced expression of Sp1, so DNMT (DNA methyltransferase) expression is also


**Table 23.** *MicroRNAs suppressing the pancreatic cancer.*


**Table 24.**

their processing is blocked [45, 46, 164]. This family is involved in the regulation of

In the myeloid leukemia, malignant blast cells are synthesized in comparison to

In another study, miR-125b (located on chromosome 1) is overexpressed in acute myeloid leukemia. The target of miR-125b is BCL2-antagonist/killer 1 (Bak1) which

In another study, miR-155 (located on chromosome 21) is overexpressed in the acute myeloid leukemia. This miR-155 is located in B cell integration cluster (BIC) gene. This BIC correlated to MYC to initiate lymphomas. Overexpression of miR-155 causes the inhibition of WEE1, a regulator of the cell cycle, and hMLH1, hMLH6, and hMLH4, the genes for mismatch repair (**Table 24**). The result of this inhibition is increased in mutation rate in progenitor and hematopoietic stem

The known biomarker for the acute myeloid leukemia is miR-29b [167]. miR-29b causes the hypomethylation of the DNA. Sp1 transcriptional factor has the binding site for both miR-29b and DNMT1. In DNMT, it binds to its promoter and

reduced expression of Sp1, so DNMT (DNA methyltransferase) expression is also

**Sr. no. MicroRNAs Potential targets Function Ref.** 1 let-7 family cyclin D1 (CCND1) Regulation of tumor [166] 2 miR-145 K-ras Growth and carcinogenesis [161]

UTR causes the

hypermethylation of the DNA is involved in tumor suppression [168]. In one study, there is overexpression of miR-204 in acute myeloid leukemia. The target of miR-204 is MEIS1 and HOXA 10 genes which disturbs the differentiation of

mononuclear cells of healthy bone marrow [167]. In myeloid leukemia the

enhance the proliferation of AML cell and prevent the apoptosis [169].

UTR for miR-29b of Sp1 (specificity protein 1). Binding to the 3<sup>0</sup>

myeloid cells. Its overexpression causes tumorigenesis [169].

In one study there is downregulation of miR-145 in pancreatic cancer. The decreased expression of miR-145 is due to activation of the K-ras gene. Expression of miR-145 causes the inhibition of expression of insulin growth factor-1 receptors (**Table 23**). Its expression causes the downregulation of genes related to cancer (SET, MCM2, SPTBN1). These genes cause growth and carcinogenesis of pancreatic

tumor by cyclin D1 (CCND1) inhibition [165, 166].

cancer [161].

**Figure 15.**

*miRNA and pancreatic cancer.*

*Current Cancer Treatment*

cells [169].

30

**Table 23.**

**22**

*MicroRNAs suppressing the pancreatic cancer.*

**5.12 Acute myeloid leukemia**

*MicroRNAs activating the acute myeloid leukemia [169].*

reduced (**Figure 16**). In acute myeloid leukemia, miR-29b results in the apoptosis when it directly targets the MCL (induced myeloid leukemia cell differentiation protein) [170]. So the expression of miR-29b is reduced in acute myeloid leukemia which leads to cancer progression as apoptosis has been decreased with reduced expression of miR-29b (**Table 25**).

#### **5.13 Ovarian cancer**

In ovarian cancer, the biomarker that is used is miR-214 and it is upregulated in cancer. It binds to the 3<sup>0</sup> UTR region of phosphatase and tensin analog (PTEN) gene and causes its hypermethylation. So this is inactivated. The direct target of PTEN is Akt protein kinase B and mediates its activation by the help of PI4K3B [171]. Akt causes the downstream effects such as activation of glycogen synthase. So when PTEN is inhibited, it activates the expression of Akt. This miR-214 resists the cisplatin-mediated cell death, so it is antiapoptotic in nature (**Figure 17**). Cisplatin is an important factor in mediating cell death [172].

In a study, there is overexpression of Hsa-miR-182 in ovarian cancer. The potential target of Hsa-miR-182 is forkhead box 3 (FOXO3) and forkhead box 1 (FOXO1) which promote the differentiation and inhibition of growth (acting as a tumor suppressor). These tumor suppressor genes are suppressed, and growth and proliferation of ovarian cell are increased (**Table 26**) [173].

**Figure 16.**

*miRNA and acute myeloid leukemia.*


**Table 25.**

*MicroRNAs suppressing the acute myeloid leukemia [170].*

also to the cell cycle along with the regulation of these genes [172]. MicroRNA is of vital importance because of its resistance to degradation and could be a potential candidate for clinical applications. However, its expression level can be screened in the serum/plasma (blood) by high-throughput sequencing technology. Further research for identification of novel microRNA will warrant the development of

microRNA-related cancer prognosis [176–180].

*MicroRNA: A Signature for Cancer Diagnostics DOI: http://dx.doi.org/10.5772/intechopen.90063*

EGFR epidermal growth factor receptor

PTEN phosphatase and tensin homolog TPM1 tropomyosin alpha-1 chain SOX4 SRY-related HMG-box

FOXO1 forkhead box protein O1

DNMT DNA methyltransferase

PKB Akt (protein kinase B)

miRISC microRNA-associated RNA-induced silencing complex DGCR8 DiGeorge syndrome chromosomal [or critical] region 8

MCL induced myeloid leukemia cell differentiation protein Mcl-1

, Sumaira Kousar1,2\*, Amer Jamil1

1 Department of Biochemistry, University of Agriculture, Faisalabad, Pakistan

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Department of Biochemistry, Government College Women University,

\*Address all correspondence to: sumairakausar@gcwuf.edu.pk

, Riaz Tabassum<sup>1</sup>

,

**Abbreviations**

CCND1 cyclin-D1

**Author details**

Ayesha Siddiqua<sup>1</sup>

Faisalabad, Pakistan

**25**

Tariq Mehmood<sup>1</sup> and Nusrat Shafiq2

provided the original work is properly cited.

**Figure 17.** *miRNA and ovarian cancer.*


#### **Table 26.**

*MicroRNAs activating the ovarian cancer.*


**Table 27.**

*MicroRNAs suppressing the ovarian cancer.*

In another study, there is downregulation of miR-200 family in ovarian cancer. The direct target of miR-200 is zinc finger E-box-binding homeobox 1 and 2 (ZEB1 and ZEB2). It prevents the EMT, metastasis, invasion, and migration of tumor cell. Interleukin-8 and CXCL1 (released from tumor epithelial cells) are also the target of miR-200 and prevent the angiogenesis of tumor cell [174].

In another study there is downregulation of miR-506 in ovarian cancer, so there is cell migration invasion of the cancer cell. When this miRNA is overexpressed, it causes the expression of E-cadherin and results in inhibition of cell invasion and migration and proliferation of ovarian cancer and, via targeting SNAI2 (E-cadherin transcriptional factor), prevents the EMT induction by *TGF-β* (**Table 27**). The miR-506 directly targets the CDK4/CDK6-FOXM1 axis and initiates the senescence [175].
