This study aims to integrate bulk and single-cell RNA sequencing data to construct a risk score model based on HOXC9-related immune genes (HRIGs) and evaluate its prognostic value in hepatocellular carcinoma (HCC).

RNA sequencing data and clinical information of HCC were obtained from TCGA and GEO databases. HRIGs were identified and a risk score model was constructed using LASSO-Cox regression analysis. The association between the risk score and tumor microenvironment was analyzed using CIBERSORT and ESTIMATE algorithms. Single-cell RNA sequencing (scRNA-seq) data were used to assess cell type distribution. Cell experiments were conducted to verify the effects of HOXC9 knockdown on HCC cell proliferation and invasion.

HOXC9 is highly expressed in HCC and associated with poor prognosis (p=0.031). The risk score model based on four HRIGs (EGLN3, IMPDH1, LPCAT1, and MARCKSL1) showed good prognostic discrimination in both TCGA and GEO cohorts, with significantly lower overall survival in the high-risk group (p<0.0001). The high-risk group exhibited higher immune scores and increased immune cell infiltration, as well as elevated immune checkpoint expression. scRNA-seq revealed increased hepatocytes and fibroblasts but decreased T/NK cells in HCC tissues. HOXC9 knockdown significantly inhibited HCC cell proliferation and invasion.

HOXC9 is overexpressed in HCC and correlates with poor prognosis. The HRIG-based risk score model effectively evaluates the prognosis and immune response in HCC patients, providing new insights for risk assessment and immunotherapy prediction.

Aryl hydrocarbon receptor (AHR) and nuclear factor-erythroid 2-related factor 2 (NRF2) can regulate a series of genes encoding the detoxifying phase I and II enzymes, via a signaling crosstalk known as the "AHR-NRF2 gene battery". The chromatin transcriptional regulator Jun dimerization protein 2 (JDP2) plays a central role in thetranscription of AHR gene in response to the phase I enzyme ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin. It forms a transcriptional complex with AHR-AHR nuclear translocator (ARNT) and NRF2-small musculoaponeurotic fibrosarcoma proteins (sMAF), which are then recruited to the respective cis-elements, such as dioxin response elements and antioxidant response elements, respectively, in the AHR promoter. Here, we present a revised description of the AHR-NRF2 gene battery as the AHR-NRF2-JDP2 gene battery for transactivating the AHR promoter by phase I enzyme ligands. The chromatin regulator JDP2 was found to be involved in the movement of AHR-NRF2 complexes from the dioxin response element to the antioxidant response element in the AHR promoter, during its activation in a spatiotemporal manner. This new epigenetic and chromatin remodeling role of AHR-NRF2-JDP2 axis is useful for identifying new therapeutic targets for various diseases, including immunological response, detoxification, development, and cancer-related diseases.

Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer, whose high frequency of relapse is often due to resistance to chemotherapy. Here, we identify inosine monophosphate dehydrogenase 2 (IMPDH2) as a contributor to doxorubicin resistance, in multiple TNBC models. Analysis of publicly available datasets reveals elevated IMPDH2 expression to associate with worse overall TNBC prognosis in the clinic, including lower recurrence-free survival post adjuvant/neoadjuvant therapy. Importantly, both genetic depletion and pharmacological inhibition of IMPDH2 leads to reduction of pro-tumorigenic phenotypes in multiple doxorubicin-resistant TNBC models, both in vitro and in vivo. Overall, we propose IMPDH2 as a novel vulnerability that could be leveraged therapeutically to suppress and/or prevent the growth of chemo-resistant lesions.

Small cell lung cancer (SCLC) is one of the highly metastatic malignancies that contributes to ∼15 % of all lung cancers. Most SCLC patients (50-60 %) develop osteolytic bone metastases, significantly affecting their quality of life. Among several factors, environmental pollutant 2,3,7,8-Tetrachlorodibenzodioxin (TCDD) and kynurenine (Kyn), an endogenous ligand derived from tryptophan (Trp) metabolism, activate the aryl hydrocarbon receptor (AhR) and are responsible for SCLC progression and metastasis. Further, elevated AhR expression in bone cells intensifies bone resorption, making the Kyn/AhR axis a potential target for the bone metastatic propensity of SCLC. We first assessed the expression profile of AhR in human SCLC cell lines and found a significantly increased expression compared to normal lung cells. Additionally, we also evaluated the clinical significance of AhR expression in the patient samples of SCLC along with the relevance of the same in the Rb1fl/fl; Trp53fl/fl; MycLSL/LSL (RPM) mouse model using immunohistochemistry and found the higher AhR expression in the patient samples and RPM mouse tumor tissues. Using computational simulations, we found that clofazimine (CLF) binds at the activator (Kyn) binding site by forming a stable complex with AhR. The CLF binding with AhR was favored by Van der Waals and hydrophobic forces, and the proteins retained their secondary structure. Furthermore, we found that Kyn treatment potentiates the migration and clonogenic ability of SCLC cell lines by activating Erk/Akt oncogenic signaling. Treatment with CLF reduces AhR expression, which inhibits Kyn-mediated proliferation of SCLC cells, induces apoptosis, and cell cycle arrest in the G2/M phase. Further, our examination indicates that Kyn treatment also promotes osteoblast-mediated osteoclast differentiation through RANKL. The treatment with CLF impedes RANKL expression and osteoclastogenesis, suggesting that CLF has the potential to be used as the therapeutic for SCLC patients having bone metastasis.

Homeobox (HOX) C9, a member of the HOX family, is an important transcription factor, and it plays a significant role in various biological processes. This family of genes is highly valued for their essential roles in establishing and maintaining the body axis during embryonic development and adult tissues. Further, HOXC9 plays a central role in neuronal differentiation, angiogenesis, and adipose distribution, which are essential for the development of the nervous system, maturation of tissues and organs, and maintenance of energy balance and metabolic health. Recent research has found that abnormal HOXC9 expression is closely associated with the development and progression of various tumor types. The HOXC9 expression level can be an indicator of tumor prognosis. Therefore, elucidating the association between HOXC9 expression and its regulatory mechanisms and tumorigenesis can provide novel insights on the diagnosis and treatment of patients with cancer.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is widely recognized to play important, but complex, modulatory roles in a variety of tumor types. In this review, we comprehensively summarize the increasingly controversial role of AhR as a tumor regulator and the mechanisms by which it alters tumor progression based on the cancer cell type. Finally, we discuss new and emerging strategies to therapeutically modulate AhR, focusing on novel agents that hold promise in current human clinical trials as well as existing FDA-approved drugs that could potentially be repurposed for cancer therapy.

Triple-negative breast cancer (TNBC) is one of the most aggressive types of cancer. Despite decades of intense investigation, treatment options remain limited, and rapid recurrence with distant metastases remains a significant challenge. Cancer cell-intrinsic production of cytokines such as type I interferons (IFN-I) is a known potent modulator of response to therapy in many cancers, including TNBC, and can influence therapeutic outcome. Here, we report that, in TNBC systems, the aryl hydrocarbon receptor (AhR) suppresses IFN-I expression via inhibition of STImulator of Interferon Genes (STING), a key mediator of interferon production. Intratumoral STING activity is essential in mediating the efficacy of PARP inhibitors (PARPi) which are used in the treatment of cancers harboring BRCA1 deficiency. We find that, in TNBC cells, PARPi treatment activates AhR in a BRCA1 deficiency-dependent manner, thus suggesting the presence of a negative feedback loop aimed at modulating PARPi efficacy. Importantly, our results indicate that the combined inhibition of PARP and AhR is superior in elevating IFN-I expression as compared to PARPi-alone. Thus, AhR inhibition may allow for enhanced IFN-I production upon PARPi in BRCA1-deficient breast cancers, most of which are of TNBC origin, and may represent a therapeutically viable strategy to enhance PARPi efficacy.