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CN-122005805-A - Application of WDR74 and/or ALYREF as molecular target in esophageal squamous cell carcinoma diagnosis and treatment

CN122005805ACN 122005805 ACN122005805 ACN 122005805ACN-122005805-A

Abstract

The invention relates to an application of WDR74 and/or ALYREF as a molecular target in diagnosis and treatment of esophageal squamous cell carcinoma, belonging to the technical field of biological medicine. Aiming at the problem that esophageal squamous cell carcinoma lacks an effective targeting treatment means, the invention discovers that the expression quantity of WDR74 in tumor tissues is obviously higher than that of beside-cancer tissues, the high expression of the WDR74 indicates that the prognosis of a patient is bad, and reveals that the specific combination of WDR74 protein and ALYREF protein exists, and the mRNA stability of EGFR is enhanced through ALYREF-mediated m 5 C RNA epigenetic modification, so that STAT3 phosphorylation is activated, and then STAT3 is combined with an apoptosis inhibitor gene MCL1 promoter region, and finally, the apoptosis is inhibited and the tumor formation is promoted. The invention provides a new molecular target and a solution for developing medicaments for treating esophageal squamous cell carcinoma targeting WDR74 and ALYREF and related diagnostic and prognostic evaluation products.

Inventors

  • WANG YANQIANG
  • CUI YONGPING
  • YAO JIALI
  • CHENG XIAOLONG
  • An Zhekun
  • ZHANG YUTONG
  • SHI XIUZHI
  • CHENG SHENGQI
  • HUI CAIXIA

Assignees

  • 山西医科大学

Dates

Publication Date
20260512
Application Date
20260214

Claims (10)

  1. 1. Use of an agent that inhibits WDR74 gene and/or ALYREF gene expression in the manufacture of a medicament for the treatment of esophageal squamous cell carcinoma.
  2. 2. The use of claim 1, wherein the agent is a small interfering RNA, the sequence of the small interfering RNA that inhibits WDR74 gene expression is shown in SEQ ID No.1, and the sequence of the small interfering RNA that inhibits ALYREF gene expression is shown in SEQ ID No. 2.
  3. The use of wdr74 protein and/or ALYREF protein as a therapeutic target for esophageal squamous cell carcinoma.
  4. Use of an inhibitor of wdr74 protein and/or ALYREF protein in the manufacture of a medicament for the treatment of esophageal squamous cell carcinoma.
  5. 5. The use according to claim 4, wherein the inhibitor of WDR74 protein and/or ALYREF protein is an antibody to WDR74 protein and/or an antibody to ALYREF protein.
  6. Use of an inhibitor of wdr74 gene and/or ALYREF gene for the preparation of a medicament for the treatment of esophageal squamous cell carcinoma.
  7. 7. The use of claim 6, wherein the inhibitors of WDR74 and ALYREF genes are small interfering RNAs.
  8. 8. A pharmaceutical composition for treating esophageal squamous cell carcinoma, comprising a pharmaceutically acceptable carrier and an effective amount of an active ingredient, wherein the active ingredient is an antibody of WDR74 protein and/or an antibody of ALYREF protein, or a small interfering RNA with a sequence shown as SEQ ID NO. 1 and/or as SEQ ID NO. 2.
  9. 9. An anticancer drug for treating esophageal squamous cell carcinoma, characterized in that the active ingredient is an inhibitor of WDR74 gene and/or ALYREF gene, or an inhibitor of WDR74 protein and/or ALYREF protein.
  10. 10. A kit for diagnosing esophageal squamous cell carcinoma or assessing prognosis thereof, comprising reagents for detecting WDR74 gene and/or ALYREF gene expression levels in a sample from a subject.

Description

Application of WDR74 and/or ALYREF as molecular target in esophageal squamous cell carcinoma diagnosis and treatment Technical Field The invention relates to the technical field of biological medicine. More particularly, the present invention relates to the use of WDR74 and/or ALYREF as molecular targets in diagnosis and treatment of esophageal squamous cell carcinoma. Background Esophageal cancer is one of the most common digestive tract malignant tumors in China, and according to epidemiological data in 2022, the incidence rate of the esophageal cancer in China is 7 th and the death rate is 5 th of all cancer types, and new cases and death cases of the esophageal cancer in China account for more than 90% of eastern Asia, wherein Esophageal Squamous Cell Carcinoma (ESCC) is the main pathological type. At present, the clinical diagnosis and treatment of ESCC still have a plurality of problems including lack of biomarkers for early diagnosis, recurrence rate and high death rate, no effective targeting treatment means, lack of accurate treatment standards for ESCC patients in China, and the like. Therefore, analyzing molecular markers in ESCC occurrence and development and mining drug targets of ESCC have important significance for promoting accurate treatment of ESCC. The WDR74 gene, WD Repeat protein 74 (WD Repeat-Containing Protein 74), belongs to one of the members of the WD40 Repeat protein superfamily. In eukaryotes, WDR74 is involved in the processing of rRNA and the synthesis of the 60S ribosomal large subunit as a ribosome assembly factor. Also, WDR74 may be involved in the development and progression of multiple cancer types. For example, in melanoma, WDR74 may activate ubiquitination degradation of the cancer suppressor gene P53 by MDM2, promoting melanoma cell proliferation. In colorectal cancer, WDR74 increases the expression of phosphorylated beta-catenin through a Wnt/beta-catenin signal pathway, thereby affecting the cell cycle and accelerating the growth of tumors. However, in ESCC, the effect of WDR74 on the malignant progression of cancer cells and the mechanism of carcinogenesis remain unknown and remain to be explored further. 5-Methylcytosine (5-methylcytosine, m 5 C) is an important type of epigenetic modification of RNA, playing a key role in the regulation of expression of tumor-associated driver genes. ALYREF as one of m 5 C recognition proteins can recognize m 5 C modification sites on specific mRNA and participate in biological processes such as stability regulation and nuclear export of target transcripts. Studies have shown that ALYREF plays a role in promoting cancer in various tumors, ALYREF enhances the stability of pyruvate kinase M2 (PKM 2) mRNA through binding to M 5 C modification site in 3' UTR region of PKM2 mRNA in bladder cancer, and further promotes tumor cell proliferation through PKM 2-mediated glycolysis, ALYREF can bind to non-coding RNA molecule LINC02159 in non-small cell lung cancer, enhances the stability of YAP1 mRNA through M 5 C modification, and further activates signal pathways of Hippo and beta-catenin to play a role in promoting cancer, and in colorectal cancer, ALYREF promotes nuclear export of RPS6KB2 and RPTOR transcripts through recruiting RNA binding protein ELAVL1 to cooperatively recognize M 5 C modification, and participates in the occurrence and development of colorectal cancer. However, the role of ALYREF in the malignant progression of ESCC and its underlying molecular mechanisms have not been elucidated to date. In summary, there are currently significant limitations to the molecular mechanism awareness of esophageal squamous cell carcinoma. On the one hand, WDR74, which is known to have a clear pro-cancerous effect in other cancer species, has a well-established mechanism of action in this disease, and on the other hand, the function of important RNA-modified reading protein ALYREF in this disease is likewise unknown. More importantly, whether two molecules, WDR74 and ALYREF, are functionally related in esophageal squamous cell carcinoma or act synergistically on a certain oncogenic pathway has never been explored. The double unknown states form fundamental difficulties in drug development for the two targets, because the criticality of the targets cannot be confirmed, the downstream paths of the targets are not clear, and the potential synergistic relationship is not clear, so that any theoretical basis cannot be provided for rational design of targeted drugs. Therefore, the system clarifies the expression, functions, mechanisms and interrelationships of WDR74 and ALYREF in esophageal squamous cell carcinoma, and becomes a key link for providing scientific preconditions for the subsequent development of targeted therapeutic strategies. Disclosure of Invention The invention aims to elucidate the cancer promotion action mechanism of WDR74 genes in esophageal squamous cell carcinoma, reveal the biological functions of ALYREF genes in the dise