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Background Previous quantitative proteomic study from our laboratory had identified leucine-rich-alpha-2-glycoprotein 1 (LRG1) as the most prominent marker for colorectal cancer (CRC). This marker was significantly up-regulated in the serum of late-stage CRC patients and present in a stage-dependent manner in the CRC cells. Many studies have linked autophagy to cancer, but none had explored the relationship between LRG1 and autophagy in CRC. This study (FRGS/1/2018/SKK08/UKM/03/3) is aimed to investigate the effect of LRG1 modulation on the autophagy mechanism in colorectal cancer. Methods Colorectal adenocarcinoma cells, HT29 (low-grade CRC) with the lowest endogenous level of LRG1 were chosen for the over-expression of human LRG1 gene, whereas colorectal carcinoma cells, HCT116 (high-grade CRC) with the highest endogenous level of LRG1 were used for the LRG1 knockdown experiment. The cells were stably transduced with lentivirus containing LRG1 open reading frame (ORFs) and short hairpin RNA (shRNA), respectively. The selection was carried out with Blasticidin S and Puromycin, respectively prior to RNA extraction and gene expression assessment via RT-qPCR. Statistical analysis of Independent T-test was performed using GraphPad Prism 8.0.1. Results Over-expression of LRG1 in HT29 increased cell proliferation by activation of Ki67 mRNA (p 0.05), but several autophagy markers (Beclin-1, ATG4D, ATG5, LC3 and GABARAP, except ATG3) were in a decreasing trend. Conclusions In summary, LRG1 enhanced the survival of low-grade colorectal cancer and tumour progression by suppression of autophagy but failed to reverse the mechanism in the knockdown model of high-grade cancer. More related works are currently on-going.

Autophagy is a conserved cellular process required to maintain homeostasis. The hallmark of autophagy is the formation of a phagophore that engulfs cytosolic materials for degradation and recycling to synthesize essential components. Basal autophagy is constitutively active under normal conditions and it could be further induced by physiological stimuli such as hypoxia, nutrient starvation, endoplasmic reticulum stress,energy depletion, hormonal stimulation and pharmacological treatment. In cancer, autophagy is highly context-specific depending on the cell type, tumour microenvironment, disease stage and external stimuli. Recently, the emerging role of autophagy as a double-edged sword in cancer has gained much attention. On one hand, autophagy suppresses malignant transformation by limiting the production of reactive oxygen species and DNA damage during tumour development. Subsequently, autophagy evolved to support the survival of cancer cells and promotes the tumourigenicity of cancer stem cells at established sites. Hence, autophagy is an attractive target for cancer therapeutics and researchers have been exploiting the use of autophagy modulators as adjuvant therapy. In this review, we present a summary of autophagy mechanism and controlling pathways, with emphasis on the dual-role of autophagy (double-edged sword) in cancer. This is followed by an overview of the autophagy modulation for cancer treatment and is concluded by a discussion on the current perspectives and future outlook of autophagy exploitation for precision medicine.