Abstract
ABSTRACT Biomarkers for predicting chemotherapy response are important for treatment of colorectal cancer (CRC) patients.SREBP1is involved in cancer cell chemoresistance, but the biological consequences of this activity in CRC are poorly understood. We set up biochemical and cell biology analyzes to analyze SREBP1 expression and chemoresistance. We found that SREBP1 was overexpressed in chemoresistant CRC samples, and that SREBP1 overexpression was correlated with poorer patient survival. Targeting SREBP1 increased chemosensitivity to gemcitabine (Gem) in CRC cells. Additionally, SREBP1 overexpression increased chemoresistance to Gem in CRC cells. SREBP1 overexpression downregulated caspase-7 and decreased CRC cell sensitivity to Gem. Low SREBP1 expression was correlated with high caspase-7 expression in CRC patient samples. Low caspase-7 expression was correlated with poor patient survival. Our findings indicated that upregulation of caspase-7 caused by downregulation of SREBP1 may be a novel prognostic biomarker, and may represent a new therapeutic target in CRC.
Highlights
Colorectal cancer (CRC) is one of the most frequent malignancies worldwide, being second in males and third in females in frequency, and ranking fourth and third for cancer-related deaths among males and females, respectively [1]
To investigate whether SREBP1 expression relates to chemosensitivity in colorectal cancer (CRC) patients, we first compared the expression levels of SREBP1 in CRC colonoscopy samples from 21 rectal cancer patients who subsequently underwent neoadjuvant chemotherapy
SREBP1a activates genes required in the synthesis of cholesterol and fatty acid, such as elongase and stearoyl-CoA desaturase, while SREBP1c directly activates the expression of more than 30 genes dedicated to the synthesis and uptake of FAs and triglycerides
Summary
Colorectal cancer (CRC) is one of the most frequent malignancies worldwide, being second in males and third in females in frequency, and ranking fourth and third for cancer-related deaths among males and females, respectively [1]. The majority of the patients with sporadic malignancies are >50 years of age;75% patients with rectal tumors and 80% patients with colon cancer being ≥60 years of age at the time of diagnosis. Include laparoscopic surgery for primary disease; resection of metastatic disease affecting, for example, the liver and lungs; radiotherapy for rectal cancer and some forms of metastatic disease; and neoadjuvant and palliative chemotherapy [3]. Despite advances in surgical and medical therapies, cure rates and long-term survival have changed little over the past several decades. Against this background, and given that CRC is preceded by a polypoid precursor, screening programs for early detection have gained momentum
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