The modulation relationship of genomic pattern of intratumor heterogeneity and immunity microenvironment heterogeneity in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, with the second highest mortality rate among all cancer types. Growing evidence has demonstrated the notable effects of intratumor heterogeneity (ITH) and tumor immune microenvironment heterogeneity (TIMH) on the biological processes involved in HCC. However, the interactive mechanisms between ITH and TIMH is still unclear. The present study systematically screened the mRNA expression, simple nucleotide variation data and clinical data of samples from The Cancer Genome Atlas (TCGA). The mutant-allele tumor heterogeneity (MATH) score was used to represent ITH, and TCGA cohort was divided into two groups according to the MATH score. Next, different immune-related signaling pathways and enriched immune-related genes were identified using Gene Set Enrichment Analysis of these two groups, and the results revealed that interleukin-1α (IL1A) and serine/threonine-protein kinase PAK4 were associated with prognosis. Furthermore, CIBERSORT was utilized to calculate the fractions of 22 types of leukocytes to represent TIMH, and the fractions of M1 and M2 macrophages were confirmed to be associated with prognosis. Therefore, PAK4, interleukin-1α (IL1A), and M1/M2 ratio were selected as the key factors involved in the interaction between ITH and TIMH. Afterwards, microRNAs (miRNAs) that were linearly related to the M1/M2 ratio and the potential target genes of the miRNAs were screened. Finally, the regulatory network between PAK4, IL1A, and the M1/M2 ratio was established, bridged by the above miRNAs and the target genes. In addition, PAK4, heat shock protein 105 kDa and miRNA-1911 were demonstrated to be a key factor involved in immune response via Weighted Correlation Network Analysis in HCC.

IGF2BP3 Enhances the Growth of Hepatocellular Carcinoma Tumors by Regulating the Properties of Macrophages and CD8+ T Cells in the Tumor Microenvironment

“…Previous bioinformatics analysis had found a correlation of IGF2BP3 expression with macrophage infiltration, and infiltration of M2 macrophages has been reported to promote HCC progression. 9 Therefore, it was hypothesized that tumor-cell derived IGF2BP3 was critical in M2 polarization. We conducted qRT-PCR to evaluate the expressions of M1 ( Nos2 , Il-1β , Tnf-α , Cxcl9 ) and M2 ( Arg1 , Ccl22 ) macrophage relevant markers in Raw264.7 cells after stimulation with culture supernatants of Igf2bp3 _wt and Igf2bp3 _ko cells for 48 hours.…”

“… 6 – 8 In HCC, M2 macrophages facilitate the migration and invasion of tumor cells and are usually associated with a poor prognosis. 3 , 9 Various cytokines and proteases secreted by M2 macrophages are involved in the inhibition of CD8 + T cells, tumor neovascularization, and tumor metastasis. 10 …”

“…[6][7][8] In HCC, M2 macrophages facilitate the migration and invasion of tumor cells and are usually associated with a poor prognosis. 3,9 Various cytokines and proteases secreted by M2 macrophages are involved in the inhibition of CD8 + T cells, tumor neovascularization, and tumor metastasis. 10 IGF2BP3, located on chromosome 7p15.3 in humans, is weakly expressed in normal adult tissue but is dramatically elevated during carcinogenesis.…”