HOXA11-AS: a novel regulator in human cancer proliferation and metastasis.

Cell growth and aberrant proliferation is the inducer of tumor occurrence and development. Metastasis is the continuation and deterioration of cancer cell proliferation and is recognized as the most terrible feature of advanced malignant neoplasm and the major cause of death in cancer patients. Obviously, the process of tumor metastasis is extremely complicated, which contains a series of metastatic cascade. 1 , 2 The tumor cells initially fall off from the primary site, then experience local infiltration, vascular invasion, blood circulation, and survival, arrest in capillaries of distant organs, colonization starts and growth is renewed. 3 , 4 A large body of genes and their products have been reported to mediate metastatic initiation and progression, such as adhesion molecules, angiogenic factors, matrix metalloproteinases, chemokines and so on. 5 – 8 More recently, miRNAs and lncRNAs also emerge to be crucial regulators in cancer proliferation and metastasis. 9 , 10 It is widely known that only 2% of the genome sequences is translated into proteins, while the remainder is the template for ncRNAs transcription. 11 , 12 Compared to miRNAs, lncRNAs exert more favorable functions in tumor malignant proliferation, invasion and migration. The novel lncRNA, HOXA11-AS , also known as HOXA11-AS1, is the homeobox (HOX) A11 antisense lncRNA. In the human genome, the HOX family of genes is characterized by highly conserved homeodomains. HOX genes are grouped into four clusters (A, B, C and D) located on four different chromosomes. HOXA11-AS gene maps to the HOXA gene cluster on chromosome 7p, which includes the protein-coding genes ( HOXA9 , HOXA10 , HOXA11 and HOXA13 ) and the genes for lncRNAs ( HOXA10-AS , HOXA11-AS and HOTTIP ). 13 , 14 As a HOXA11 antisense lncRNA, HOXA11-AS may participate in embryo implantation, endometrial development and cervix carcinogenesis by regulating HOXA11 . 15 – 17 Increasing evidences have shown that HOXA11-AS can be a novel regulator in the proliferation and metastasis of diverse human cancers. 18 – 21 Research identifications prove that numerous lncRNAs can serve as molecular signals, decoys, guides and scaffolds, exerting their functional roles via epigenetic modification or transcriptional activation/suppression in the nucleus. For instance, lncRNA GClnc1 promotes gastric tumorigenesis, invasiveness and metastasis by acting as a modular scaffold of WDR5 and KAT2A complexes and specifying the histone modification pattern on the target genes. 22 The lncRNA MALAT1 can be a molecular decoy through binding to SFPQ and releasing the oncogene PTBP2 from SFPQ/PTBP2 complex, thus accelerating colorectal cancer (CRC) growth and metastasis. 23 In addition, lncRNAs also emerge as ceRNAs by sponging microRNAs, and sometimes bind with specific proteins to maintain mRNA stability or induce mRNA decay, thus participating in posttranscriptional processing in the cytoplasm. 24 – 26 Dramatically, HOXA11-AS can regulate human cancer cell growth and metastasis both transcriptionally and posttranscriptionally and turn to be cancer biomarkers and therapeutic targets. In our review, we will summarize the biological functions, molecular mechanisms and clinical significance of HOXA11-AS in diverse human cancers.

Aforementioned reports prove that HOXA11-AS expression levels in majority of tumors are increased. Table 1 summarizes the HOXA11-AS -associated clinicopathologic features, such as patients’ tumor size, TNM stage and lymph node metastasis, which emphasizes the evolvement of HOXA11-AS in human cancer diagnosis. As shown in Table 1 , aberrant expression of HOXA11-AS is also implicated as a prognostic biomarker in different cancer types. In particular, Li et al 64 and Mu et al 65 separately conducted a meta-analysis exploring HOXA11-AS to be a potential biomarker for metastasis and patients’ prognosis in malignancies.

Malignant proliferation of cancer cells and metastasis propel the progression of carcinoma deterioration. Separately, cancer metastasis is a complicated multistep process that often contributes to patients’ postoperative recurrence and poor prognosis. Recent theoretical and practical research states that EMT can elucidate partial reasons for cancer invasion and dissemination. The entire EMT process includes loss of epithelial cell characteristics and acquisition of mesenchymal characteristics. During this transformation, the mesenchymal markers increase, including Snail , Slug, N-cadherin and Vimentin . On the contrary, decreased E-cadherin is the most common epithelial marker in EMT. 66 , 67 Noticeably, EMT course is exactly included in partial HOXA11-AS -modulated metastasis of cancers such as NSCLC, CC, and BC. The expression levels of several canonical EMT molecular markers, E-cadherin , N-cadherin, Snail , β-catenin and Vimentin , were changed after loss of or gain of HOXA11-AS . The functional characteristics of HOXA11-AS in various human cancers are all summarized in Table 2 . The ceRNA theory serves as a posttranscriptional way, which can explain the regulatory mode of lncRNA–miRNA– mRNA. The lncRNAs function as ceRNAs sponging for miRNAs, thus affecting the expression levels of miRNAs target genes. 68 , 69 As expected, HOXA11-AS can sponge for various miRNAs in different cancers ( Table 2 ). Certainly, apart from ceRNA-modulatory pattern, HOXA11-AS simultaneously interacts with EZH2/LSD1/DNMT1, epigenetically modifying the target genes in cancer. Besides relevant reports in tumor field, HOXA11-AS was also discussed to be a skin-related lncRNA, which was involved in Wnt pathways in keloids. 70 Additionally, HOXA11-AS was found to take part in the progression of fracture healing by sponging miR-124 -3 p. 71 Moreover, HOXA11-AS also plays important roles in adipocyte differentiation and endometriosis in women. 72 , 73 To conclude, HOXA11-AS is a newly identified lncRNA in various human carcinomas and other diseases, but the functions and molecular mechanisms are still not fully characterized, which deserve to be further excavated in the future.