MCOLN1 Promotes Proliferation and Predicts Poor Survival of Patients with Pancreatic Ductal Adenocarcinoma

Abstract

Background. MCOLN1 (mucolipin subfamily, member 1) was first identified as an autophagic regulator, which was essential for efficient fusion of both autophagosomes and late endosomes with lysosomes. This study is aimed at investigating the role of MCOLN1 in the development of pancreatic ductal adenocarcinoma (PDAC). Methods. Immunohistochemistry (IHC) assay was conducted to evaluate the expression level of MCOLN1 in 82 human PDAC tumor tissues. Overall survival (OS) and recurrence-free survival (RFS) analysis was performed to assess the prognosis of patients. Colony formation and MTT assays [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] were performed to measure the proliferation capacity of tumor cells. The expression level of related genes was measured by RT-PCR (reverse transcription polymerase chain reaction) and western blot assays. The animal model was used to examine the effects of indicated protein on tumorigenesis in vivo. Results. The results of IHC showed that a high level of MCOLN1 expression was associated with the poor clinical characteristics of PDAC patients. OS and RFS were significantly worse in patients with high MCOLN1 expression. Silencing of MCOLN1 dramatically blocked the proliferation of PDAC cells. Mechanism studies confirmed that knockdown of MCOLN1 decreased the expression of Ki67 and PCNA (proliferating cell nuclear antigen), two markers of cell proliferation. In vivo, MCOILN1 depletion reduced the formation and growth of tumors in mice. Conclusion. The high level of MCOLN1 expression was associated with poor clinical outcomes of PDAC patients. MCOLN1 ablation could inhibit PDAC proliferation of both in vitro and in vivo, which provide a new insight and novel therapeutic target for the treatment of PDAC.

TRPML1—Emerging Roles in Cancer

“…In non-small-cell lung cancer, increased TRPML1 expression is observed at high tumor stages and is positively correlated with tumor proliferation, migration, and invasion [ 26 ]. Consistent with this finding, TRPML1 expression is also increased in pancreatic ductal adenocarcinoma (PDAC) patients and negatively correlates with patient overall survival and recurrence-free survival [ 27 ]. Since cancer cells aggressively augment protein synthesis machineries to stimulate cell proliferation, cancer cells experience elevated proteotoxic stress due to increased occurrences of translational infidelity and susceptibility to protein misfolding in the endoplasmic reticulum, potentially triggering cell death [ 28 , 29 ].…”

Endolysosomal TRPMLs in Cancer

“…Yin et al [ 122 ] found that the expression of TRPML1 increases along with the progression of human nonsmall-cell lung cancer (NSCLC). Similarly, by evaluating the expression levels of TRPML1 in tumor tissues from 82 pancreatic ductal adenocarcinoma (PDAC) patients, Hu et al found that a higher TRPML1 expression level is associated with the poor clinical characteristics of these PDAC patients [ 123 ]. Compared with patients with low TRPML1 expression, patients with high TRPML1 expression have significantly lower overall survival.…”

“…Compared with patients with low TRPML1 expression, patients with high TRPML1 expression have significantly lower overall survival. A role of TRPML1 in PDAC progression is further confirmed by using a cell model showing that the proliferation of PDAC cells is dramatically blocked by TRPML1 depletion, and by using a mouse model showing that TRPML1 is required for the formation and growth of PDAC tumors [ 123 ]. Collectively, these studies suggest that TRPML1 is often upregulated in cancer cells to promote tumorigenesis.…”

ElevatedMCOLN1Expression in p53-Deficient Bladder Cancer is Necessary for Oncogene-Induced Cell proliferation, Inflammation, and Invasion

“…While insufficient endolysosomal function is associated with inborn errors of metabolism, lysosomal storage, and degenerative diseases, increased biogenesis of these organelles is a recurring theme in cancers (Davidson and Vander Heiden, 2017). Several studies have described roles for the endolysosomal cation channel, TRPML1, in different malignancies (Hu et al, 2019;Kasitinon et al, 2019;Xu et al, 2019;Yin et al, 2019). A common theme in these studies is that TRPML1 is necessary for malignancy promoting signaling cascades involving RAS-MAPK and mTORC1.…”

“…Since inhibition of TRPML1 arrests proliferation or induces cell death in cancers with elevated expression of the CLEAR network genes (Hu et al, 2019;Jung and Venkatachalam, 2019;, tumors with hyperactivated TFEB/TFE3/MITF signaling are addicted to TRPML1.…”