HOXB4 Mis-Regulation Induced by Microcystin-LR and Correlated With Immune Infiltration Is Unfavorable to Colorectal Cancer Prognosis

Abstract

Microcystin-LR (MC-LR) exists widely in polluted food and water in humid and warm areas, and facilitates the progression of colorectal cancer (CRC). However, the molecular mechanism associated with the MC-LR-induced CRC progression remains elusive. The purpose of this study is to explore the role of the hub genes associated with MC-LR-induced CRC development at the molecular, cellular and clinical levels through bioinformatics and traditional experiments. By utilizing R, we screened and investigated the differentially expressed genes (DEGs) between the MC-LR and the control groups with the GEO, in which, HOXB4 highly expressed in MC-LR-treated group was identified and further explored as a hub gene. With the aid of TCGA, GEPIA, HPA, UALCAN, Cistrome, and TIMER, the increased mRNA and protein levels of HOXB4 in CRC tissue were found to be positively associated with high tumor stage and poor prognosis, and were linked to immune infiltration, especially tumor-associated macrophages and cancer-associated fibroblasts. Cox regression analysis and nomogram prediction model indicated that high HOXB4 expression was correlated to poor survival probability. To elucidate the mechanism of high HOXB4 expression induced by MC-LR, we overlapped the genes involved in the MC-LR-mediated CRC pathways and the HOXB4-correlated transcription genes. Importantly, C-myc instead of PPARG and RUNX1 promoted the high expression of HOXB4 through experiment validation, and was identified as a key target gene. Interestingly, C-myc was up-regulated by HOXB4 and maintained cell cycle progression. In addition, MC-LR was proved to up-regulate HOXB4 expression, thus promoting proliferation and migration of Caco2 cells and driving the cell cycle progression. In conclusion, MC-LR might accelerate CRC progression. In the process, MC-LR induced C-myc augmentation elevates the high expression of HOXB4 through increasing the S phase cell proportion to enhance Caco2 cell proliferation. Therefore, HOXB4 might be considered as a potential prognostic biomarker for CRC.

Identification of stemness-related LncRNA signature for predicting the prognosis and therapy response in colorectal cancer

“…8G-8L), which is consistent with previous studies reporting that high HOXB4 expression promotes cell proliferation and migration, drives cell cycle progression, and is associated with poorer survival probability. In addition, studies have shown that HOXB4 is involved in immune in ltration, especially in tumor-associated macrophages and cancer-associated broblasts [32]. Our analysis of the tumor immune microenvironment indicated that patients with high HOXB4 expression have high in ltration in some immune cells (such as CD8 T cells, macrophages, NK cells, etc.…”

Identification of differentially expressed genes and enriched pathways in inflammatory bowel disease using bioinformatics and next generation sequencing data analysis

“…ERBB2 [114], CAV1 [152], SOCS3 [150], HNF4A [133], hsamir-449a [503], hsa-mir-21 [504], NUCKS1 [505], NANOG (Nanog homeobox) [506], IRF8 [507] and SMAD4 [508] were a diagnostic markers of ulcerative colitis and could be used as therapeutic targets. ERBB2 [172], BIRC3 [192], IFIT1 [509], SPRY2 [222], MAPK14 [306], E2F1 [325], CDC25A [294], CAV1 [301], BCL6 [297], CDKN1A [326], SOCS3 [293], HNF4A [244], hsa-mir-449a [503], hsa-mir-375 [510], hsa-mir-21-5p [511], hsa-mir-21 [512], NUCKS1 [513], HOXB4 [514], MECOM (MDS1 and EVI1 complex locus ) [515], NANOG (Nanog homeobox) [506], DNAJC2 [516], RAD21 [517], IRF8 [507] and SMAD4 [518] were found to be substantially related to gastrointestinal cancers. BIRC3 [482] , RPS26 [501], HOXB4 [519] and SMAD4 [520] might be associated with the prognosis of anemia.…”

Structural insight into the substrate-binding mode and catalytic mechanism for MlrC enzyme of Sphingomonas sp. ACM-3962 in linearized microcystin biodegradation

“…During the overgrowth of HCBs, toxin-producing cyanobacteria release various microcystins (MCs) into the water body, with MC-LR, MC-RR, and MC-YR being the most toxic and widely distributed MC variants (Hoeger et al, 2007;Atencio et al, 2008;Zeller et al, 2012;Okogwu et al, 2014;He et al, 2018;Tao et al, 2018;Zhang et al, 2021). MCs are potent liver toxins and tumor promoters (Fujiki and Suganuma, 1994;Zhang et al, 2012;Tian et al, 2013;Wang et al, 2014Wang et al, , 2022Hernandez et al, 2021). These cyanotoxins are extremely stable and are not effectively removed by conventional methods.…”