MIR4435-2HG Is a Potential Pan-Cancer Biomarker for Diagnosis and Prognosis

Abstract

The lncRNA MIR4435-2 host gene (MIR4435-2HG) is located on human chromosome 2q13, and its expression is up-regulated in 18 tumors. MIR4435-2HG participates in 6 signaling pathways to promote tumorigenesis, including the TGF-β signaling pathway, Wnt/β-catenin signaling pathway, MDM2/p53 signaling pathway, PI3K/AKT signaling pathway, Hippo signaling pathway, and MAPK/ERK signaling pathway. MIR4435-2HG competitively binds with 20 miRNAs to form a complex ceRNA network, thereby regulating the expression of downstream target genes. The high expression of MIR4435-2HG is also closely related to the clinicopathological characteristics and poor prognosis of a variety of tumors. Also, the high expression of MIR4435-2HG in peripheral blood or serum has the value of predicting the risk of 9 tumors. In addition, MIR4435-2HG participates in the mechanism of action of three cancer drugs, including resveratrol for the treatment of lung cancer, cisplatin for non-small cell lung cancer and colon cancer, and carboplatin for triple-negative breast cancer. This article systematically summarizes the diagnostic and prognostic value of MIR4435-2HG in a variety of tumors and outlines the ceRNA network and signaling pathways related to MIR4435-2HG, which will provide potential directions for future MIR4435-2HG research.

Keywords: MIR4435-2HG; cancer; competing endogenous RNA; diagnosis; prognosis.

Figure 1

A pan-cancer analysis of MIR4435-2HG. (A) MIR4435-2HG is dysregulated in 32 cancer types. (*** means p < 0.001, ** means p<0.01, * means p<0.05, ns means no significant difference); (B) quantile expression of MIR4435-2HG in 32 cancer types; (C) The correlation tests between MIR4435-2HG expression and methylation of MIR4435-2HG CpG sites (*** means p<0.001, ** means p<0.01, * means p<0.05). ACC, Adrenocortical carcinoma; ALL, Acute lymphoblastic leukemia; AML, Acute myeloid leukemia; BLCA, Bladder urothelial carcinoma; BRCA, Breast invasive carcinoma; CESC, Cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, Cholangiocarcinoma; COAD, Colon adenocarcinoma; ESCA, Esophageal carcinoma; GBM, Glioblastoma multiforme; HNSC, Head and Neck squamous cell carcinoma; KICH, Kidney chromophobe; KIRC, Kidney renal clear cell carcinoma; KIRP, Kidney renal papillary cell carcinoma; LGG, Brain lower grade glioma; LIHC, Liver hepatocellular carcinoma; LUAD, Lung adenocarcinoma; LUSC, Lung squamous cell carcinoma; NBL, Neuroblastoma; OV, Ovarian serous cystadenocarcinoma; PAAD, Pancreatic adenocarcinoma; PCPG, Pheochromocytoma and Paraganglioma; PRAD, Prostate adenocarcinoma; READ, Rectum adenocarcinoma; SARC, Sarcoma; STAD, Stomach adenocarcinoma; SKCM, Skin cutaneous melanoma; TGCT, Testicular germ cell tumors; THCA, Thyroid carcinoma; THYM, Thymoma; UCEC, Uterine corpus endometrial carcinoma; UCS, Uterine carcinosarcoma.

Figure 2

The role of MIR4435-2HG in digestive system cancer. In the digestive system, MIR4435-2HG can promote the growth of 5 types of tumors, including oral squamous cell carcinoma (OSCC), esophageal squamous cell carcinoma (ESCC), hepatocellular carcinoma (HCC), gastric cancer (GC), and colorectal cancer (CRC). By regulating downstream genes, MIR4435-2HG can affect tumor cell proliferation, migration, invasion, apoptosis, EMT, and cell cycle.

Figure 3

The role of MIR4435-2HG in tumors of the respiratory system, reproductive system, urinary system, and nervous system. MIR4435-2HG can also affect the proliferation, migration, invasion, apoptosis, EMT, and cell cycle of tumor cells by regulating downstream genes. Tumor of the respiratory system consists of lung cancer (LC); Tumors of the reproductive system consist of ovarian cancer (OC), cervical cancer (CC), breast (BC), and prostate cancer (PCa); Tumors of the urinary system include clear cell renal cell carcinoma (ccRCC) and bladder cancer (BCa); and tumor of the nervous system includes gliomas.

Figure 4

The mechanism of MIR4435-2HG affecting the behavior of tumor cells in other Systems. MIR4435-2HG can promote the progression of tumors in other systems, and affect the proliferation, invasion, migration, apoptosis, and EMT of tumor cells. Affecting EMT and cell cycle is an important mechanism for MIR4435-2HG to promote tumorigenesis. Head and neck squamous cell carcinoma (HNSC); T-cell acute lymphoblastic leukemia (T-ALL); nasopharyngeal carcinoma (NPC).

Figure 5

The signaling pathways involved in MIR4435-2HG. In human tumors, MIR4435 participates in at least 6 signaling pathways, including the TGF-β signaling pathway, Wnt/β-catenin signaling pathway, MDM2/p53 signaling pathway, PI3K/AKT signaling pathway, Hippo signaling pathway, and MAPK/ERK signaling pathway.

Figure 6

The ceRNA network of MIR4435-2HG. MIR4435-2HG can interact with 19 miRNAs in at least 14 cancers and osteoarthritis, and regulate the expression of its downstream target genes. HCC, Hepatocellular carcinoma; CRC, Colorectal cancer; OSCC, Oral squamous cell carcinoma; GC, Gastric cancer; NSCLC, Non-small cell lung cancer; GBM, Glioblastoma; BCa, Bladder cancer; ccRCC, clear cell renal cell carcinoma; OC, Ovarian cancer; CC, Cervical cancer; HNSC, Head and neck squamous cell carcinoma.

Figure 7

The role of MIR4435-2HG in cancer drugs. In lung cancer, MIR4435-2HG may be involved in the inhibitory effect of resveratrol on the growth of lung cancer cells. In non-small cell lung cancer (NSCLC) and colon cancer, MIR4435-2HG may be a driving factor for cisplatin resistance. In triple-negative breast cancer (TNBC), MIR4435-2HG may be involved in the development of carboplatin resistance.