Abstract
Background Preoperative chemoradiotherapy (pCRT) is a common and essential therapeutic strategy for patients with locally advanced rectal cancer (LARC), but poor tumor response and therapeutic resistance to chemoradiotherapy have appeared usually among persons and affected those patients' survival prognosis. The resistance to chemoradiotherapy in rectal cancer is difficult to predict. This study was aimed at evaluating the role of V-set and transmembrane domain containing 2 like protein (VSTM2L) in resistance to chemoradiotherapy in rectal cancer. Methods Analysis of the GEO profiling datasets of rectal cancer patients receiving pCRT disclosed that VSTM2L as a candidate gene was significantly upregulated in nonresponders of rectal cancer with pCRT. The mRNA and protein expression of VSTM2L was detected by quantitate real-time PCR, western blotting, and immunohistochemistry in six rectal cancer biopsy tissues before pCRT. Furthermore, the rectal cancer patient-derived organoids were cultured to evaluate the association of VSTM2L expression and tumor response to CRT. Overexpression of VSTM2L in cancer cells treated with CRT was analyzed for the function of cell proliferation and viability, clone formation, DNA damage repair, and apoptosis ability. The GSEA and RNA-sequence analysis were used to find the downstream mechanism of VSTM2L overexpression in cells treated with CRT. Results The mRNA levels of VSTM2L were significantly downregulated in normal rectal tissues compared to tumor tissues and were upregulated in nonresponders of rectal cancer patients receiving pCRT and positively correlated with poor survival prognosis from GEO datasets. High expression of VSTM2L was significantly associated with tumor regression after pCRT (P = 0.030). Moreover, high expression of VSTM2L reduced γ-H2AX expression in rectal cancer patient-derived organoids treated with CRT. The overexpression of VSTM2L in colorectal cancer cells induced resistance to CRT via promoting cell proliferation and inhibiting apoptosis. The molecular mechanism revealed that the overexpression of VSTM2L induced resistance to CRT through downstream IL-4 signaling affecting the progress of cell proliferation and apoptosis. Conclusion The high expression of VSTM2L induced resistance to CRT, and adverse survival outcomes served as a prognostic factor in patients with rectal cancer receiving pCRT, suggesting that VSTM2L high expression may be a potential resistant predictable biomarker for LARC patients receiving pCRT.
Highlights
Colorectal cancer (CRC) is viewed as the third most common cancer and the fourth cancer-related mortality in men and women worldwide [1]
We have found that there were nine genes significantly identified in upregulation of nonresponders to Preoperative chemoradiotherapy (pCRT), including C6orf15, KRT23, COL2A1, FOLR1, FREM1, DACT2, NKD2, VSTM2L, and ZSCAN18 (Figure 1(a))
VSTM2L gene was chosen for further investigation because its mRNA expression is significantly relative to both the survival time (OS) and disease-free time (DFS) in the GSE87211 dataset about rectal cancer patients receiving pCRT (Supplementary Figure)
Summary
Colorectal cancer (CRC) is viewed as the third most common cancer and the fourth cancer-related mortality in men and women worldwide [1]. It is important to identify potential biomarkers of locally advanced rectal cancer patients for prediction in tumor response to pCRT for further treatment of novel target therapies. Preoperative chemoradiotherapy (pCRT) is a common and essential therapeutic strategy for patients with locally advanced rectal cancer (LARC), but poor tumor response and therapeutic resistance to chemoradiotherapy have appeared usually among persons and affected those patients’ survival prognosis. The rectal cancer patient-derived organoids were cultured to evaluate the association of VSTM2L expression and tumor response to CRT. The mRNA levels of VSTM2L were significantly downregulated in normal rectal tissues compared to tumor tissues and were upregulated in nonresponders of rectal cancer patients receiving pCRT and positively correlated with poor survival prognosis from GEO datasets. The overexpression of VSTM2L in colorectal cancer cells induced resistance to CRT via promoting cell proliferation and inhibiting apoptosis. The high expression of VSTM2L induced resistance to CRT, and adverse survival outcomes served as a prognostic factor in patients with rectal cancer receiving pCRT, suggesting that VSTM2L high expression may be a potential resistant predictable biomarker for LARC patients receiving pCRT
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