Colorectal cancer (CRC) is a neoplasm caused by the uncontrolled development of cells located in the layers of the colon wall [1]. It is estimated that CRC is among the main types of cancer with the highest incidence and mortality worldwide, according to Globocan statistics. In Mexico, it is in third position both in terms of incidence and mortality [2]. CRC is a multifactorial disease, the pathogenesis of which is not fully understood. At present, several risk factors have been identified, including age, ethnicity, genetic mutations, epigenetic factors, dietary factors, smoking and alcohol consumption [3]. Several studies have shown that its occurrence and development are closely related to the inactivation of tumor suppressor genes, oncogene activation, apoptosis imbalance and cell proliferation [4, 5]. Non-coding RNAs (ncRNAs) have recently gained attention because of their involvement in different biological processes. An increasing number of studies have demonstrated that mutations or abnormal expression of ncRNAs are closely associated with various diseases, including CRC [6, 7].
HOTAIR is a long non-coding RNA (lncRNA) that has been linked to cancer development, progression, and metastasis [8]. It has been observed that the overexpression of HOTAIR can contribute to the progression of multiple cancers, including ovarian, breast, pancreatic, hepatocellular, lung, gastric, and colorectal cancers [9]. In addition, there is growing evidence that HOTAIR expression levels may be useful as a prognostic and predictive cancer biomarker [8]. It has also been suggested that HOTAIR may function as a molecular decoy in tumors, where it may sequester RNA binding proteins (RBPs) and several microRNAs (miRNAs) [8]. Peng et al. have suggested that HOTAIR may play a role in accelerating colorectal cancer development by down-regulating miRNA-34a [10].
A considerable number of studies have suggested that variants in the HOTAIR gene may serve as potential genetic markers for cancer susceptibility [11, 12]. Some studies have demonstrated that the rs920778 T > C variant is associated with an increased susceptibility to developing cancer, including breast cancer [13, 14], lung cancer [14], oral cancer [15], and colorectal cancer [16]; however, the results remain controversial.
miRNAs are short and non-coding sequences of approximately 20–24 nucleotides that play an important role in post-transcriptional regulation, which can affect the stability and translation of several mRNA [17]. Recent studies have demonstrated that miRNAs are capable of modulating up to 60% of protein-coding genes in the human genome [18]. Consequently, due to their pivotal role in gene regulation, miRNAs are implicated in numerous and significant processes that facilitate the maintenance and homeostasis of the tissues [19], through the regulation of the proliferation [20], differentiation [21], apoptosis [22], and hematopoiesis [23]. Most miRNAs are situated in genomic regions that frequently undergo rearrangements as amplifications or deletions, indicating that abnormalities in miRNAs play a significant role in carcinogenesis [24].
miR-3117 is located at the human chromosome 1 and produces the miR-3117-3p, which has affinity for genes involved in the mitogen-activated protein kinase (MAPK) pathway [25]. Alterations in this pathway have been described in several types of cancer, including colorectal cancer [26, 27]. The role of the rs7512692 and rs4655646 polymorphisms with respect to the miRNA-3117 in cancer has only been investigated in acute lymphoblastic leukemia [25, 28] and breast cancer [29]. In CRC, these variants have not been analyzed.
This study aims to investigate, for the first time, the allele, genotype, and haplotype distribution of the HOTAIR gene (rs920778) and the miR-3117 gene (rs7512692 and rs4655646 variants); and to assess the potential association of these gene variants with the clinicopathological characteristics and the development of CRC in Mexican patients.