Oncogenicity of LHX4 in colorectal cancer through Wnt/β-catenin/TCF4 cascade

Abstract

The LHX genes play an important role in a number of developmental processes. Potential roles of LHXs have been demonstrated in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and types. The aim of this study was to investigate the function role of LHXs in the human colorectal cancer (CRC). The gene expression changes of LHXs in CRC tissues compared with noncancerous colorectal tissues was detected using real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) analysis and immunohositochemistry. And we identified the gene LHX4 that were significantly upregulated in CRC by QRT-PCR analysis and immunohistochemistry. Furthermore, we discovered that LHX4 promoted cancer cell proliferation in vitro, and LHX4 expression correlated with elevated β-catenin levels in CRC and β-catenin function was required for LHX4's oncogenic effects. Mechanistically, LHX4 facilitate TCF4 to bind to β-catenin and form a stable LHX4/TCF4/β-catenin complex and transactive its downstream target gene. LHX4 mutations that disrupt the LHX4-β-catenin interaction partially prevent its function in tumor cells. All in all, LHX4 is a commonly activated tumor promoter that activate Wnt/β-catenin signaling in cancer cells of CRC.

<p>LHX6 Affects Erlotinib Resistance and Migration of <em>EGFR</em>-Mutant Non-Small-Cell Lung Cancer HCC827 Cells Through Suppressing Wnt/β-Catenin Signaling</p>

“…29 LHX4 may be involved in the tumorigenesis of colorectal cancer and leukemia. 30,31 LHX9 was detected to be frequently silenced in pediatric malignant astrocytomas by hypermethylation and this epigenetic alteration was found to contribute to glioma cell migration and invasiveness. 32 LHX6 expression was found to be downregulated or silenced with hypermethylation status in both lung cancer cell lines and tissues, and LHX6 overexpression caused suppression of cell viability, colony formation and migration and induction of apoptosis and G1/S arrest in lung cancer 95D and H358 cell lines, as well as inhibition of lung cancer cell tumorigenicity in nude mice through upregulating p21 and p53 expression, and downregulating Bcl-2, cyclinD1, c-myc, CD44, and MMP7 expression.…”

FGF-induced LHX9 regulates the progression and metastasis of osteosarcoma via FRS2/TGF-β/β-catenin pathway

“…Previous study found that LHX2 and LHX4 could modulate the carcinogenicity and metastasis of various tumors through β-catenin/TCF4 pathway [7, 24], so we wonder whether the homologous LHX9 had similar function in OS. To address this question, we then perform western blot to probe the expression of related proteins in BMP4 and Wnt signaling pathways, such as BMP4, β-catenin, COL1A1, Snail-1, Slug-1, MMP-1, Twist1 and MMP-9, all of which were involved in the metastasis process [16–18, 26, 29, 47].…”

“…Afterwards, we performed co-immunoprecipitation assay and the data elucidated that LHX9 could interact with beta-catenin (Fig. 9), similarly, LHX4 has also been reported to bind to beta-catenin, which then translocated into cell nuclear and facilitated the association of TCF4 with LHX4/beta-catenin complex, and the complex could transactive downstream genes involved in the progression of human colorectal cancer [7]. Based on our experiments and previous reports, we speculated that LHX9 promoted the nuclear translocation of beta-catenin through their interaction, which then facilitated gene expression that were controlled by beta-catenin and boosted OS progression and metastasis.

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“…In addition, LHX9 expression was found to be reduced during the development of gliomas in children, which was correlated with the migration and invasion of glioma [43]. As for other LHX members, early studies revealed that LHX2 promoted tumor cell proliferation in pancreatic ductal adenocarcinoma, and LHX4 facilitated the development of colorectal cancer, both via enhancing Wnt/TCF4/β-catenin pathway [7, 55]. Therefore, the function of LHXs may vary in different tumors and in different status of tumor development.…”

Therapeutic strategies targeting Wnt/β‑catenin signaling for colorectal cancer (Review)

“…Additionally, negative regulatory targets inhibit cRc progression via inactivating Wnt/β-catenin signaling, and these targets include tumor suppressor genes (167,168), metastasis-suppressor genes (169), ubiquitin-like proteins (170) and anticancer bioactive peptides (171). In the present review, the effects of these therapy targets on cRc in the Wnt/β-catenin signaling pathway are presented in Table II (3,4,21,35,52,60,105,(160)(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171)(172)(173)(174)(175)(176)(177)(178).…”