Mechanistic and Functional Shades of Mucins and Associated Glycans in Colon Cancer

Pothuraju, Ramesh; Krishn, Shiv Ram; Gautam, Shailendra K.; Pai, Priya; Ganguly, Koelina; Chaudhary, Sanjib; Rachagani, Satyanarayana; Kaur, Sukhwinder; Batra, Surinder K.

doi:10.3390/cancers12030649

Cited by 46 publications

(42 citation statements)

References 135 publications

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“…28 Studies have shown that the putative underlying mechanisms of MUC5AC neo-expression include promotor hypomethylation. 11 MUC5AC transcription is also directly and indirectly regulated by various cancer-associated transcription factors (eg AP-1, SP-1, NF-kB, HNF-5a-alpha) and pathways (eg MAPK, Akt/ PI3K) [39][40][41] as well as by several mediators of inflammation (IL-1-beta, IL-6, TNF-alpha, IL-13). [41][42][43][44] Tumor types that are always MUC5AC negative are of diagnostic interest, because a positive MUC5AC immunostaining will virtually exclude such entities from diagnostic considerations.…”

Section: Discussionmentioning

confidence: 99%

MUC5AC Expression in Various Tumor Types and Nonneoplastic Tissue: A Tissue Microarray Study on 10 399 Tissue Samples

Rico

Mahnken

Büscheck

et al. 2021

Technol Cancer Res Treat

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Background: Mucin 5AC (MUC5AC) belongs to the glycoprotein family of secreted gel-forming mucins and is physiologically expressed in some epithelial cells. Studies have shown that MUC5AC is also expressed in several cancer types suggesting a potential utility for the distinction of tumor types and subtypes. Methods: To systematically determine MUC5AC expression in normal and cancerous tissues, a tissue microarray containing 10 399 samples from 111 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results: MUC5AC was expressed in normal mucus-producing cells of various organs. At least weak MUC5AC positivity was seen in 44 of 111 (40%) tumor entities. Of these 44 tumor entities, 28 included also tumors with strong positivity. MUC5AC immunostaining was most commonly seen in esophageal adenocarcinoma (72%), colon adenoma (62%), ductal adenocarcinoma of the pancreas (64%), mucinous carcinoma of the ovary (46%), diffuse gastric adenocarcinoma (44%), pancreatic ampullary adenocarcinoma (41%), intestinal gastric adenocarcinoma (39%), and bronchioloalveolar carcinoma (33%). Clinically relevant tumors with complete or almost complete absence of MUC5AC staining included small cell carcinoma of the lung (0% of 17), clear cell renal cell carcinoma (0% of 507), papillary thyroid carcinoma (0% of 359), breast cancer (2% of 1097), prostate cancer (2% of 228), soft tissue tumors (0.1% of 968), and hematological neoplasias (0% of 111). Conclusion: The highly standardized analysis of a broad range of cancers identified a ranking order of tumors according to their relative prevalence of MUC5AC expression.

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Section: Discussionmentioning

confidence: 99%

MUC5AC Expression in Various Tumor Types and Nonneoplastic Tissue: A Tissue Microarray Study on 10 399 Tissue Samples

Rico

Mahnken

Büscheck

et al. 2021

Technol Cancer Res Treat

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“…Mucins may be membrane tethered, secretory, or non-gel forming. Their production and secretion are principally mediated by goblet cells and may be influenced by nonspecific factors such as immune system interactions with microbiota and dietary factors, and specific modulators including epigenetics and transcriptional factors [27]. Among the various pathogen recognition receptor (PRR) ligands, toll-like receptor (TLR) ligands serve as particularly powerful stimuli for goblet cell production of mucins [28].…”

Section: Physical Barriermentioning

confidence: 99%

Microbiota-Immune Interactions in Ulcerative Colitis and Colitis Associated Cancer and Emerging Microbiota-Based Therapies

Popov

Caputi

Nandeesha

et al. 2021

IJMS

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Ulcerative colitis (UC) is a chronic autoimmune disorder affecting the colonic mucosa. UC is a subtype of inflammatory bowel disease along with Crohn’s disease and presents with varying extraintestinal manifestations. No single etiology for UC has been found, but a combination of genetic and environmental factors is suspected. Research has focused on the role of intestinal dysbiosis in the pathogenesis of UC, including the effects of dysbiosis on the integrity of the colonic mucosal barrier, priming and regulation of the host immune system, chronic inflammation, and progression to tumorigenesis. Characterization of key microbial taxa and their implications in the pathogenesis of UC and colitis-associated cancer (CAC) may present opportunities for modulating intestinal inflammation through microbial-targeted therapies. In this review, we discuss the microbiota-immune crosstalk in UC and CAC, as well as the evolution of microbiota-based therapies.

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“…Expression/secretion of mucin proteins is often altered in colon cancer (64,65 characterized by abundant mucin secretion comprising at least 50% of the tumor volume (2). Mucin (MUC2) is the predominantly secreted mucin synthesized by colonic goblet cells (37), and its overexpression is frequently found in MAC (35).…”

Section: Filip1l Knockdown Induces Mucin Secretion In Colon Cancer Mediated By Pfdn1mentioning

confidence: 99%

FILIP1L Loss Is a Driver of Aggressive Mucinous Colorectal Adenocarcinoma and Mediates Cytokinesis Defects through PFDN1

et al. 2021

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Aneuploid mucinous colorectal adenocarcinoma (MAC) is an aggressive subtype of colorectal cancer with poor prognosis. The tumorigenic mechanisms in aneuploid MAC are currently unknown. Here we show that downregulation of Filamin A interacting protein 1-like (FILIP1L) is a driver of MAC. Loss of FILIP1L increased xenograft growth, and, in colon-specific knockout mice, induced colonic epithelial hyperplasia and mucin secretion. The molecular chaperone prefoldin 1 (PFDN1) was identified as a novel binding partner of FILIP1L at the centrosomes throughout mitosis. FILIP1L was required for proper centrosomal localization of PFDN1 and regulated proteasome-dependent degradation of PFDN1. Importantly, increased PFDN1, caused by downregulation of FILIP1L, drove multi-nucleation and cytokinesis defects in vitro and in vivo, which were confirmed by time-lapse imaging and 3D cultures of normal epithelial cells. Overall, these findings suggest that downregulation of FILIP1L and subsequent upregulation of PFDN1 is a driver of the unique neoplastic characteristics in aggressive aneuploid MAC. STATEMENT OF SIGNIFICANCEThis study identifies FILIP1L as a tumor suppressor in mucinous colon cancer and demonstrates that FILIP1L loss results in aberrant stabilization of a centrosome-associated chaperone protein to drive aneuploidy and disease progression.Approximately half of MAC tumors are aneuploid (3-7), whereas the remainder are diploid and associated with microsatellite instability. Aneuploid MAC tumors were shown to be clinically more aggressive than diploid tumors (8,9). Compared to common colorectal adenocarcinoma, MAC has an entirely different molecular "signature", as well as an aberrant and aggressive metastatic pattern that is associated with poor response to treatment and worse prognosis (2). The mechanisms of MAC tumorigenesis are currently unknown.Filamin A interacting protein 1-like (FILIP1L) is a tumor suppressor that we identified in several types of cancer, including CRC (10-13). We showed that FILIP1L expression is down-regulated by promoter methylation (10, 12), a key mechanism of tumor suppressor down-regulation in cancer. Down-regulation of FILIP1L is associated with chemo-resistance and worse prognosis in ovarian and colon cancer (14,15). Moreover, its expression is inversely correlated with the invasive/aggressive potential of tumors and with epithelial-to-mesenchymal (EMT) marker expression (11,16). Its structural homologies and centrosomal localization suggest that FILIP1L may bind to elements of the cytoskeleton, and chaperone proteins to proteasomes (11,17,18).The prefoldin1 (PFDN1) chaperone is overexpressed in multiple cancer types and is associated with poor prognosis in colon cancer (19,20). PFDN1 participates in a multimeric prefoldin complex that facilitates proper folding of key cytoskeletal components such as actin and tubulins.Loss of PFDN1 decreases tubulin levels, thereby reducing microtubule growth and causing defects in cell division and embryonic lethality (21), though the mechanisms are unkno...

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Mechanistic and Functional Shades of Mucins and Associated Glycans in Colon Cancer

Cited by 46 publications

References 135 publications

MUC5AC Expression in Various Tumor Types and Nonneoplastic Tissue: A Tissue Microarray Study on 10 399 Tissue Samples

MUC5AC Expression in Various Tumor Types and Nonneoplastic Tissue: A Tissue Microarray Study on 10 399 Tissue Samples

Microbiota-Immune Interactions in Ulcerative Colitis and Colitis Associated Cancer and Emerging Microbiota-Based Therapies

FILIP1L Loss Is a Driver of Aggressive Mucinous Colorectal Adenocarcinoma and Mediates Cytokinesis Defects through PFDN1

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