PAUF/ZG16B promotes colorectal cancer progression through alterations of the mitotic functions and the Wnt/β-catenin pathway

Abstract

Pancreatic adenocarcinoma upregulated factor (PAUF), also known as ZG16B, was previously found in the secretome of metastatic colorectal cancer cells. Here, we demonstrated the presence of PAUF at the intracellular level and its multiple effects on cancer progression. An initial decline of PAUF expression was observed at early stages of colorectal cancer followed by an increase at the metastatic site. PAUF was located at different cellular compartments: membraneassociated vesicles, endosomes, microtubule-associated vesicles, cell growth cones and the cell nucleus. PAUF loss in two colorectal cancer cell lines caused severe alterations in the cell phenotype and cell cycle, including tetraploidy, extensive genomic alterations, micronuclei and increased apoptosis. An exhaustive analysis of the PAUF interactome using different proteomic approaches revealed the presence of multiple components of the cell cycle, mitotic checkpoint, Wnt pathway and intracellular transport. Among the interacting proteins we found ZW10, a moonlighting protein with a dual function in membrane trafficking and mitosis. In addition, PAUF silencing was associated to APC loss and increased β-catenin nuclear expression. Altogether, our results suggest that PAUF depletion increases aneuploidy, promotes apoptosis and activates the Wnt/β-catenin pathway in colorectal cancer cells facilitating cancer progression. In summary, PAUF behaves as a multifunctional protein, with different roles in cancer progression according to the extra-or intracellular expression, suggesting a therapeutic value for colorectal cancer.

Identification and Verification of Core Genes in Colorectal Cancer

“…Zymogen granule protein 16 (ZG16) is a soluble protein that is expressed only in epithelial cells of the small intestine, rectum, and colon [36]. Studies have shown that ZG16 is downregulated in colorectal cancer, which is consistent with the results of our analysis [37][38][39]. However, the detailed molecular mechanism of ZG16 in colorectal cancer is still unknown.…”

<p>A Novel Prognostic Score Based on <em>ZG16</em> for Predicting CRC Survival</p>

“…In general, the results are in line with multiple previous studies, which indicated that loss of ZG16 expression may make a great difference in CRC development and worse OS. [18][19][20][21] In fact, the TNM system based on the depth of tumor invasion (T), the number of affected lymph nodes (N), and the presence of metastasis (M) remains the most common prognostic indicator for stratifying patients. However, survival rates are highly heterogeneous for even patients who are within the same TNM stage.…”

Circulating tumor cell characterization of lung cancer brain metastasis in the cerebrospinal fluid through single-cell transcriptome analysis

“…Among the nine genes with biased expression in the earlier stage P8-1 ( Supplementary Table 6), MSMB (microseminoprotein beta, Figure 6d) is one of the most abundant proteins in semen (123)(124)(125) and it has been used for diagnosis of prostate cancer (126). ZG16B/PAUF (pancreatic adenocarcinoma-upregulated factor, Figure 6D) is a secreted protein with crucial role in pancreatic ductal adenocarcinoma (PDAC) (127)(128)(129)(130), as well as other cancer types including epithelial ovarian cancer (131), cervical carcinoma (132), colorectal cancer (133) and oral squamous cell carcinoma (134). KLK5 (Kallikrein-related peptidases 5, Figure 6D) is in the same gene family as the prostate-specific antigen KLK3, exerts key modulatory effects on many cancers (135)(136)(137)(138)(139) and it is selectively inhibited by SPINK, a family of serine peptidase inhibitor kazal type, which bind to their target serine proteases and inhibit their proteolytic function (140)(141)(142)(143)(144)(145).…”