Open access peer-reviewed chapter - ONLINE FIRST
By Begum Rokeya, Mohammad Asrafuzzaman, Maliha Tabassum Rashid and Shaeri Nawar
Submitted: September 8th 2020Reviewed: February 20th 2021Published: April 6th 2021
DOI: 10.5772/intechopen.96754
Downloaded: 21
Cancer and inflammation are connected by intrinsic pathways and extrinsic pathway where the intrinsic pathway is activated by genetic events including mutation, chromosomal rearrangement or amplification, and the inactivation of tumor-suppressor genes, as well as the extrinsic pathway, is the inflammatory or infectious conditions that increase the cancer risk. On the other hand, introns are non-coding elements of the genome and play a functional role to generate more gene products through splicing out, transcription, polyadenylation, mRNA export, and translation. Moreover, introns also may act as a primary element of some of the most highly expressed genes in the genome. Intron may contain their regulatory function as CRISPR system which is activated after the demand of specific gene for specific protein formation where those are required for gene expression, they go for transcription and rest of them form splicing. This chapter will focus on the plausible role of introns to influence the genetic events of inflammation-mediated cancer cell development.
The functioning links between cancer and inflammation was approached by a great scientist and physician Rudolf Ludwing Carl Virchow in 1863 [1, 2, 3]. Thereafter, for long Virchow’s idea had almost been unevaluated and discussed insufficiently [1]. Balkwill and colleagues (2001) supported Virchow’s idea and stated that if molecular deregulation is the “match that lights the fire” of cancer, then some types of inflammation may act as the fuel that stimulates the flame. For instance, the inflammatory process act as a cofactor in malignancy in the bladder, cervical, ovarian, gastric, MALT (mucosa-associated lymphoid tissue) lymphoma, esophageal, colorectal, hepatocellular, bronchial, mesothelioma, and Kaposi sarcoma [3].
Currently, it is scientifically proven that inflammation promotes all stages of tumor formation as well as the development of cancer where chronic inflammation or non-resolving inflammation is playing a principal role in the initiation, promotion, malignant transformation, invasion and metastasis of cancer [4, 5, 6, 7, 8, 9]. Interestingly, cancer-related inflammation is representing its 7th position as a cancer hallmark and catching the current research attention in human cancer biology [5]. Basically, Inflammation act on cancer development by linking extrinsic and intrinsic pathway [9]. The extrinsic pathway develops inflammatory condition or microenvironment by inflammatory leukocytes particularly macrophages and soluble mediators (vasoactive amines such as histamine and serotonin, peptide such as bradykinin, and eicosanoids such as thromboxanes, leukotrienes, and prostaglandins) that raises cancer risk [9, 10, 11]. Intrinsic pathway is driven by genetic events (e.g. oncogenes, genetic aberrations) causing neoplastic transformation, initiate the expression of inflammation-related programs which guide the construction of an inflammatory microenvironment [11]. Inflammatory system involves the dynamic regulations of hundreds of genes and complex transcriptional program [12]. Moreover, the gene regulations by intron are often expressed in most of the cell through the effects of splicing or specific features [13, 14, 15]. Recently, several scientific reports claim that retained intron deregulates splicing machine in tumor transcriptoms [16, 17, 18]. Intron retention is considered as mis-splicing in which rather than being spliced out intron stays back and retained in mature mRNA [17]. However, the broad gap exists in monitoring of introns role in understanding of gene expression which could be a powerful tool in biotechnological and therapeutic applications. This chapter will cover intron’s role in the development of inflammation, intron retaining genes causing inflammation to cancer and finally unfolding of a hypothesis about CRISPR like machine to monitor introns function.
Inflammation is activated by leukocytes which make inflammatory mediators in the extrinsic pathway and this pathway is also triggered by various infections and toxic agents such as gastric acid reflux, autoimmune disease etc. [9]. Patients with inflammatory bowel diseases have an increased chance of getting colorectal cancer. As an example, about 43% of patients with ulcerative colitis develop colorectal cancer [19]. Moreover,
Intrinsic pathway is activated by genetic variation such as proto-oncogene activation, inactivated tumor suppressor genes, and chromosomal multiplication as well as mutation which develops neoplasia [22]. A gene coding protein namely tyrosine kinase RET shows rapid and ample genetic variation in human papillary thyroid carcinoma (PTC) and initiates the transcriptional program that links to the development of inflammation [33]. Transcriptome profile is activated by tyrosine kinase RET in human papillary carcinoma and comprises with colony-stimulating factors (CSFs), interleukin 1β (IL-1β), cyclo-oxygenase 2 (COX2), chemokines attacking monocytes and dendritic cells (CCL2 & CCL20), angiogenicchemokines (CXCL8), matrix-degrading enzymes and inhibitors, chemokine receptor (CXCR4) [34]. For example, patients with lymph nodes metastasis have shown an elevated level of tyrosine kinase RET activated inflammatory molecules in their biopsy results which demonstrate that genetic events have taken place in the pathogenesis of tumor and constructed an inflammatory environment [33, 34, 35]. Moreover,
Intron is defined as any intervening nucleotide sequence that formed splicing at the RNA level [39]. Intron was first discovered in 1970s with a traditional views that the coding region of eukaryotic genes are interrupted by introns which are spliced out from pre mature mRNA transcripts before the formation of mature mRNA [39, 40, 41]. After the elucidation of intron splicing mechanism, scientist became excited about its function on gene expression and speculated that may be introns carry out some function like regulation of splicing function, regulation of transcription, evolutionary function or coding capacity but there was no clear examples of their active functions on gene expression [41]. From the starting 21st century, many researches have claimed about the intron function on gene expression or intron mediated enhancement of gene expression [13, 42, 43, 44, 45, 46, 47]. However, a question remains unclear that within the genome, who is responsible to remember or decide which intron or parts of nucleotide sequences are necessary to stay within the mature mRNA stand for inflammatory gene expression rather than form splicing that result in cancer? Current chapter sheds light on the above question and hypothesize CRISPR like machine in perspective of inflammation mediated cancer development.
After the discovery of alternative splicing (AS), the transcriptomic and proteomic complexity has increases significantly [47, 48]. Recent breakthrough studies in high-throughput sequencing have explored a pivotal role of AS in normal biology that more than 95% of human multi exonic genes are subject to AS and produce at least two alternative isoforms [49, 50]. Moreover, Braunschweig and colleague compared 11 vertebrate species and observed that about 50–75% of multi-exonic genes are affected by intron retention (IR) which is one kind of AS [47, 48, 51]. While another study showed that IR affects near about 80% of protein coding genes in humans [52]. Some scientific reports also considered IR as a harmful process for the body by slowing down splicing kinetics and delaying the onset of gene expression, by raising pre-mRNA degradation in the nucleus through nuclear exosomes and finally by enhancing cytoplasmic pre-mRNA degradation through nonsense-mediated decay [51, 53, 54]. This statement is also supported by the Green and colleague’s research as the genes that encoded the regulators of macrophage transcription, signaling inflammation, and phagocytosis has increased their expression when the IR events decreased [55]. As it is known, that intron retention (IR) is the process where instead of typically being spliced out, the introns remain intact in the mature mRNAs and thus whole process of IR supposedly has numerous physiological drawbacks resulting in different diseases [47, 48].Currently, many researchers strongly claim that IR is a key mechanism to control gene expression during the development, differentiation and activation of several types of mammalian cell [56, 57, 58, 59, 60, 61, 62, 63]. A recent study by Green and colleague claimed that intron retention affected the expression of key genes
| Gene name | Protein name | General function | Types of cancer that is developed by IR gene | Abnormal function | References |
|---|---|---|---|---|---|
| TGFB Induced Factor Homeobox 2 | TGF-β-induced factor homeobox 2 ( | Ovarian cancer | Over expressed | [64, 65] | |
| Epstein–Barr nuclear antigen 3 | This gene plays a principle role for activation and immortalization of human B-cells. Represses transcription of viral promoters TP1 and Cp interact with RBPJ and also inhibits the | Lymphoma and Epithelial cancers | Amplication | [66, 67] | |
| Apolipoprotein E4 | This gene gives instructions to make a protein called apolipoprotein E. This protein combines with fats (lipids) in the human body to form molecules called lipoproteins. Lipoproteins in body package cholesterol and other fats and transfer them by the bloodstream. | Breast cancer | Increased frequency | [68, 69] | |
| Epidermal growth factor receptor | Receptor tyrosine kinase binding ligands of the EGF family. They activate a lot of signaling cascades to transform them extracellular cues into appropriate cellular responses. | Lung cancer | Mutation or cell damage | [70, 71] | |
| Receptor Tyrosine Kinase | Ovarian cancer, cholangiocarcinoma, inflammatory myofibroblastic tumor, colorectal, and angiosarcoma | Mutation | [72, 73] | ||
| RUNX Family Transcription Factor 1 | The protein encoded by this gene represents the alpha subunit of CBF(Core binding factor) and is thought to be involved in the development of normal hematopoiesis. Chromosomal translocations involving by this gene are well-documented and have been associated with several types of leukemia. Three transcript variants encoding different isoforms have been found for this gene | Myeloid and lymphoid | Mutation | [74, 75] | |
| Tumor Protein 53 | Breast cancer, bone and soft tissue sarcomas, brain tumors and adrenocortical carcinomas (ADC), leukemia, stomach cancer and colorectal cancer | Gene Alternation or Deletion or Mutation | [76, 77] |
List of intron retention genes and their functions.
PCR technique revealed two alternate splice forms of
The expression of the
It was claimed that 2340 and 1422 genes show tumor-specific and normal tissue-specific retention events respectively [89, 90]. For example,
Intron retention frequency may be responsible to inactive tumor suppressor genes in many cancers cell [93]. Study revealed that in cancerous condition, retained intron transcript exits in NMD pathway and inactivates the
The evolutionary history and relationship of an organism or group of species are named phylogeny. Phylogeny depicts the connection of an organism. Phylogenetic relationships give information on shared common ancestry but not obligatory how organisms are similar or different. Phylogenic tree analysis of all genes those are performing intron retention scenario, PcGs and Ras oncogenes (Figures 1–3) has done to find out the relation among the genes. MEGA X software has been used to construct the phylogenic tree to understand the relation among all the cancers genes (Tables 1 and 2).
Phylogenetic tree of intron retaining (IR) genes.
Phylogenic tree between
Phylogenic tree among IR gene, RAS oncogenes and PcGs.
| Gene name | Protein name | General function | Types of cancer that is developed by IR gene | Abnormal function | References |
|---|---|---|---|---|---|
| B-lymphoma Moloney murine leukemia virus insertion region-1 | This gene functions through chromatin remodeling as a principle epigenetic repressor of numerous regulatory genes involved in embryonic development and self-renewal in somatic stem cell and also plays a median role in DNA damage repair. It is an oncogene and abnormal expression is related with multiple cancers and resistance to certain chemotherapies. | Gastric, ovarian, breast, head and neck, pancreatic and lung cancer, primary hepatocellular carcinoma (HCC) and endometrial carcinoma | Over expression | [95, 96] | |
| Chromobox proteins 7 | This gene encodes a protein that comprises the CHROMO (CHRomatin Organization MOdifier) domain. It is thought to control the lifespan of several normal human cells. | Breast, Thyroid, Colorectal, Pancreas, Lung carcinoma and Glioblastoma | Down regulation | [97, 98] | |
| Phenylalanine Hydroxylase | This gene gives instructions for making an enzyme called phenylalanine hydroxylase. This enzyme is responsible for the primary step in processing phenylalanine, which is a building block of proteins (an amino acid) obtained through the diet. | Liver cancer | Down regulation | [99, 100] | |
| Ring Finger 1A | This gene encodes proteins characterized by a RING domain, a zinc-binding motif related to the zinc finger domain. The gene product can bind DNA and can act as a transcriptional repressor. It is related with the multimericpolycomb group protein complex. | Hepatocellular and colorectal carcinomas | Down regulation | [101, 102] | |
| Polycomb group ring finger 2 | Breast cancer, Prostate cancer | Loss of expression and down regulation | [103, 104] | ||
| Enhancer of zeste homolog-2 | The | Breast cancer, Colorectal cancer, Endometrial cancer, Gastric cancer, Liver cancer, Lung cancer | Over expression | [105, 106] | |
| Embryonic ectoderm development | This gene encodes a member of the Polycomb-group family. It maintains the transcriptional repressive state of genes over successive cell generations. This protein interacts with enhancer of zeste 2, the cytoplasmic tail of integrin beta7, immunodeficiency virus type 1 (HIV-1) MA protein, and histone deacetylase proteins. This protein mediates repression of gene activity through histone deacetylation, and may act as a specific regulator of integrin function. Two transcript variants encoding distinct isoforms have been identified for this gene. | Colorectal Cancer, acute myeloid leukemia and diffuse large B cell lymphoma | High expression | [107, 108, 109] | |
| suppressor of zeste 12 homolog | This zinc finger gene has been detected at the breakpoints of a recurrent chromosomal translocation reported in endometrial stromal sarcoma. Recombination of these breakpoints results in the fusion of this gene and | Colorectal, ovarian and non-small lung cancer, head and neck squamous cell carcinoma | Over expression | [110, 111] | |
| PHD fing protein 19 | Hepatocellular carcinoma, glioma, and ovarian cancers, glioblastoma progression, prostate cancer | Over expression | [112, 113] | ||
| TumourProtein 53 | Functions are the same as discussed in Table 1 | Types of cancers are the same as discussed in Table 1 | Gene alternation or deletion or mutation | [76, 77] | |
| Kirsten rat sarcoma viral oncogene | The | Non-small cell lung cancer, colorectal cancer, and pancreatic cancer | Mutation | [114, 115] |
List of PcGs genes and their functions.
Figure 1 demonstrates that the vertical line on the left side is the common ancestor or the root of the seven gene sequences from which the genes have been evolved in a period. The evolution period can be explained through the horizontal lines near the sequences. The small length of lines before sequences means the sequences evolved in a short period whereas the long length of lines means longer time was needed for the sequences to be evolved. The common ancestor or root has been divided into two branch points. From the first branch point total of five sequences have been modified which were
Figure 2 depicts that both type of cancer genes (
Figure 3 demonstrates that all the genes were evolved from a common ancestor. The IR gene
CRISPR-Cas9 is also known as a genome-editing tool where CRISPR stands for “Clustered Regularly Interspaced Short Palindromic Repeats and Cas9 is an enzyme that cuts foreign DNA [116]. In the 21st century, CRISPR-Cas9 is being used immensely in medical technology to edit, remove or add a gene to correct genetic defects [116]. CRISPR has conformed from the natural defense mechanism of bacteria, archaea and developed an immune system by CRISPR loci [116]. CRISPR and Cas9 enzyme serve as an immune guard and provide safety against bacteriophage, viruses, and foreign invaders [117, 118, 119]. The immunization process after invading foreign genetic elements, a small fragments of foreign DNA are integrated into the CRISPR repeat-spacer array within the host chromosome as new spacers. Thus, a genetic record of prior infection will save into the host body that enables to prevent future invasion of the same invader [120, 121] (Figure 4).
CRISPR biology.
The nucleotide repeats and spacers are main two component of CRISPR. Repeated sequence of nucleotide is distributed in the CRISPR region and Spacers are a small portion of DNA present in the CRISPR region. Destruction of foreign invading DNA or RNA occurs by Cas9 enzyme. If in future, the foreign body again attacks the organism, they fight it off as they have the virus or foreign invader’s DNA from beforehand and thus they recognize it and kill it [121]. So in CRISPR biology, spacer acts as a responsible sequence to remember or decide which foreign body needs to be killed where Cas9 enzyme plays a pivotal role. According to our hypothesis, intron network might work as CRISPR like functioning model.
According to the section 3, it is confirmed that IR have the ability to influence inflammation mediated cancer development. From the CRISPR function it is clear that according to the demand of the cell, CRISPR can get activated. It might be possible that according to the demand of the abnormal cells, intron retention may form to confirm inflammation mediated malignancy state (Figure 5). Moreover, our phylogenetic tree analysis depicts that PcGs,
Illustration of retained intron in the gene causing mutation which leads to inflammation and tumorigenesis resulting in development of cancer.
Cancer is a genetic disease and is one of the leading causes of death around the world. As a genetic event, the intron retention causes inflammation as well as the development of cancer cells. So far, it is clear that the intron is spliced away during gene expression while exons remain and express the genes. However, the retention of introns is an unlikely phenomenon that differs from the common hypothesis and appears anomalous. The genes involved in retaining intron have a carcinogenic effect. It may be speculated that some nucleotide sequence whether it is coding or non-coding region could function as a memory sequence, hence are able to remember intronic sequence as like spacer responsibility of CRISPR system and would only be functioning according to the demand of the cell. Future in depth analysis on intron retaining genes is required to explore their effect on inflammation and cancer.
We gratefully acknowledge Asian Network of Research on Antidiabetic Plants (ANRAP) and Bangladesh University of Health Sciences (BUHS) for providing all types of logistic facilities to conduct this work.
Vascular endothelium growth factor Papillary thyroid carcinoma colony-stimulating factors Interleukin 1β Cyclo-oxygenase 2 Polycomb complex target genes Alzheimer’s disease Clustered Regularly Interspaced Short Palindromic Repeats Alternative splicing Intron retention Chronic obstructive pulmonary disease Mucosa-associated lymphoid tissue
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