KR-20260067471-A - Pharmaceutical composition for the prevention or treatment of cancer via modulating the expression of HN1

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC) through the regulation of HN1 expression. The present invention demonstrated that the inhibition of HN1 significantly inhibits tumor growth, and that this is achieved through the inhibition of the activation of the SREBP-1-mediated lipid synthesis pathway. The present invention can be usefully employed to effectively inhibit the progression of HCC by significantly inhibiting tumor growth through the inhibition of HN1, reducing metastatic and invasive capabilities, and inducing apoptosis of tumor cells.

Inventors

• 김수미
• 맹약우
• 김화
• 이총삼

Assignees

• 전북대학교산학협력단

Dates

Publication Date

20260513

Application Date

20241105

Claims (13)

1. A pharmaceutical composition for the prevention or treatment of cancer comprising HN1 shRNA consisting of the nucleotide sequences of SEQ ID NOs 1 to 3 as an active ingredient.
2. In paragraph 1, A pharmaceutical composition for the prevention or treatment of cancer, characterized in that the cancer is hepatocellular carcinoma (HCC).
3. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of cancer, characterized by reducing the expression of one or more of PARP and caspase-9.
4. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of cancer, characterized by promoting cell cycle arrest of cancer cells.
5. In paragraph 4, The above composition is a pharmaceutical composition for the prevention or treatment of cancer, characterized by reducing the expression of one or more of the group consisting of cyclin D1, CDK4, and CDK6.
6. In paragraph 4, The above composition is a pharmaceutical composition for the prevention or treatment of cancer characterized by increasing the expression of p53.
7. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of cancer, characterized by reducing the expression of one or more of uPA and vimentin.
8. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of cancer, characterized by reducing the expression of one or more of the group consisting of NQO1, GSTA5, GPR150, SPP1, HN1, UBASH3B, GSTA1, DLK1, HEPACAM, and GSTA2.
9. In paragraph 1, A pharmaceutical composition for the prevention or treatment of cancer, characterized by increasing the expression of one or more of the group consisting of PAX6, UGT2B10, SLC16A9, DKK1, UGT2B11, WDR72, UGT2B28, and PRSS8.
10. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of cancer, characterized by inhibiting the phosphorylation of Akt.
11. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of cancer, characterized by reducing the expression of one or more of SREBP1 and SREBP2.
12. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of cancer, characterized by inhibiting the production of cholesterol and triglycerides in cancer cells.
13. In paragraph 1, The above composition is a pharmaceutical composition for the prevention or treatment of cancer, characterized by inhibiting the expression of one or more of FAS and ACC.

Description

Pharmaceutical composition for the prevention or treatment of cancer via modulating the expression of HN1 The present invention relates to a pharmaceutical composition for the prevention or treatment of hepatocellular carcinoma (HCC) through the regulation of HN1 expression. Cancer is the leading cause of morbidity and mortality worldwide. Liver cancer accounts for over 800,000 deaths globally, making it the sixth most prevalent malignant tumor and the second leading cause of cancer-related mortality. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and is associated with increased mortality in individuals with liver cirrhosis. HCC can develop progressively within a healthy liver due to various risk factors, including hepatitis B and C, aflatoxin exposure, cirrhosis, alcohol consumption, anabolic steroid use, and hemochromatosis. Currently, liver transplantation and surgical resection are the primary treatments for HCC patients; however, postoperative prognosis still varies depending on individual patient factors and health status. Furthermore, the growing concern over recurrence after treatment poses an obstacle to achieving optimal treatment outcomes. Clinical staging systems are currently a useful method for predicting the prognosis of hepatocellular carcinoma patients and classifying them based on observable physical signs and symptoms. However, predictive accuracy remains limited, and the relationship between the biological characteristics and clinical variability of hepatocellular carcinoma has not been identified. The hematological and neurological expressed 1 (HN1) gene exhibits high expression levels in various cancer types, including melanoma, prostate cancer, breast cancer, and thyroid cancer. HN1 is associated with tumor growth stimulation and the progression of metastatic carcinomas, and has been shown to play a pivotal role in neurodevelopment, neuroregeneration, and retinal regeneration. In particular, depletion of HN1 inhibits cell cycle arrest in both melanoma and prostate cells. Previous studies identified a total of 1,016 and 628 genes, respectively, as being associated with the survival of hepatocellular carcinoma patients after surgery. In these two studies, 65 genes were selected that were closely correlated with high risk scores, an increased risk of liver cancer development, and an unfavorable prognosis for liver cancer patients. An investigation into the expression patterns of these 65 genes revealed that hepatocellular carcinoma patients with elevated HN1 expression experienced overall poor survival times and a relatively high likelihood of recurrence. Another study demonstrated that five gene scores based on the composite expression levels of HN1, RAN, RAMP3, KRT19, and TAF9 are complexly linked to the biology and prognosis of hepatocellular carcinoma, showing that hepatocellular carcinoma patients exhibiting overexpression of these five gene scores had the lowest survival rates. Despite these results suggesting a role for HN1 in HCC, specific biological functions of HN1 have not yet been elucidated. Furthermore, the molecular mechanisms governing how HN1 regulates the proliferation and invasion of HCC cells and its interactions with signaling pathways have not been clearly elucidated. The present invention aimed to elucidate the fundamental molecular mechanisms by which HN1 controls the proliferation, invasion, metastasis, and intracellular metabolism of HCC cells and to utilize this for the treatment and improvement of HCC. Figure 1 shows the relationship between HN1 overexpressed in human HCC, poor prognosis, and promoter methylation. Figure 2 shows the effect of HN1 on cell proliferation and death in HCC. Figure 3 shows the effect of HN1 on the cell cycle of HCC. Figure 4 shows the effect of HN1 on cell migration and infiltration of HCC. Figure 5 shows the change in gene expression levels in HCC caused by HN1 knockdown. Figure 6 shows the regulation of HN1 by Akt in HCC. Figure 7 shows the regulation of SREBP-1 and SREBP-2 by HN1 in HCC. Figure 8 shows the control of lipid formation by HN1 in HCC. Figure 9 shows the control of HN1 proliferation and lipid production through SREBP-1 in HCC. Figure 10 shows that tumor formation was inhibited upon HN1 knockdown in xenograft mice. The following examples will be explained in more detail. However, these examples are intended to illustrate one or more specific examples, and the scope of the present invention is not limited to these examples. Cell culture and patient tissue The HCC cell lines Hep3B, HLE, Huh7, SNU368, SHJ-1, HepG2, and SNU449 used in this study were cultured as a monolayer in DMEM (Gibco by life technologies, Thermo Fisher Scientific Inc., Waltham, MA, USA) supplemented with 10% fetal bovine serum (FBS, Welgene, Gyeongsan, South Korea) and 1% penicillin (Sigma, St. Louis, MO, USA) in 100 nm dishes under standard conditions of 37°C and 5% CO2. Liver tissue samples from the patients were obtained fr