Mechanistic Study for Inhibiting Aggressive Behavior in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the second primary cause of cancer death, accounting for almost 1 million fatalities per year. Despite continuous advancements in surgical and therapeutic procedures, the 5-year survival rate of advanced CRC patients remains exceedingly low because to resistance, recurrence, and metastasis. To overcome obstacles, it is vital to comprehend the mechanisms of aggressive behavior in CRC. In Part I, I focused on cancer stem-like cell (CSC) populations, which have been linked to an increased risk of cancer recurrence and metastasis. I explored the molecular mechanism of niclosamide, an FDA-approved anthelmintic medication, as a powerful Wnt inhibitor capable of suppressing tumor development CSC populations. To gain a molecular understanding, I investigated how Wnt suppression by niclosamide selectively targets CSCs. As a result, I discovered that nicosamide downregulates several Wnt signaling components, notably lymphoid enhancer-binding factor 1 (LEF1) expression, which is important for regulating stemness. Following that, I discovered that the doublecortin-like kinase 1 (DCLK1)-B is a target of LEF1 and increases cancer stemness in CRC cells. The disruption of the LEF1/DCLK1-B axis by niclosamide resulted in the elimination of cancer stemness as well as therapeutic effects on CRC initiation, progression, and resistance. These findings provide a preclinical justification for expanding niclosamide's clinical evaluation for the treatment of aggressive CRC. In part II, I focused on soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), a large protein family required for membrane fusion and vesicular trafficking; nevertheless, their possible role in cancer malignancy has been unknown. I investigated the expression patterns of SNARE genes in CRC tissues and discovered that SEC22B expression, a vesicle SNARE, was significantly higher in tumor cells than in normal tissues, with a more significant rise in metastatic tissues. SEC22B knockdown significantly reduced CRC cell survival and proliferation, particularly under stressful conditions such as hypoxia and serum deprivation, as well as the amount of stress-induced autophagic vacuoles. Furthermore, in a CRC cell xenograft mice model, SEC22B knockdown successfully reduced liver metastasis, with histological evidence of decreased autophagic flux and proliferation inside cancer cells. This work suggests that SEC22B plays a critical role in increasing the aggressiveness of CRC cells, implying that SEC22B could be a promising therapeutic target for aggressive CRC. Collectively, these two separate methodologies have been integrated to provide mechanistic insight into the challenge of how to treat aggressive CRC and provided new possible therapeutic targets for improving treatment choices that are now available.