The RNA‐binding protein LARP4 regulates cancer cell migration and invasion

Abstract

LARP4 is a La‐related RNA‐binding protein implicated in regulating mRNA translation, which interacts with poly(A)‐binding protein (PABP). We previously identified LARP4 in an RNAi screen as one of several genes that regulate the shape of PC3 prostate cancer cells. Here we show that LARP4 depletion induces cell elongation in PC3 cells and MDA‐MB‐231 breast cancer cells. LARP4 depletion increases cell migration and invasion, as well as inducing invasive cell protrusions in 3D Matrigel. Conversely, LARP4 over‐expression reduces cell elongation and increases cell circularity. LARP4 mutations are found in a variety of cancers. Introduction of some of these cancer‐associated mutations, including a truncation mutant, into LARP4 enhances its effects on cell morphology. The truncation mutant shows enhanced interaction with PABP. We propose that LARP4 inhibits migration and invasion of cancer cells, and that some cancer‐associated mutations stimulate these effects of LARP4. © 2016 The Authors. Cytoskeleton Published by Wiley Periodicals, Inc.

Circular RNA LARP4 correlates with decreased Enneking stage, better histological response, and prolonged survival profiles, and it elevates chemosensitivity to cisplatin and doxorubicin via sponging microRNA‐424 in osteosarcoma

“…11 Another experiment illuminates that LARP4 inhibits prostate cancer cell migration and invasion. 24 As for the prognostic value of circ-LARP4, a previous cohort study reports that circ-LARP4 expression is decreased in tumor tissue than that in paired adjacent tissue, and is negatively correlated with Federation of Gynecology and Obstetrics stages and survival in ovarian cancer patients, which is partially in line with our results. 25 In this study, we found that circ-LARP4 was upregulated in non-tumor tissue compared with tumor tissue, and tumor tissue circ-LARP4 high expression was associated with decreased Enneking stage, elevated good response rate, and more satisfactory survival profiles in osteosarcoma patients.…”

“…And the LARP4 gene, the location of circ‐LARP4, has also been found to be a tumor suppressor, for example, a recent experiment elucidates that LARP4 gene represses cell motility and migration in ovarian cells . Another experiment illuminates that LARP4 inhibits prostate cancer cell migration and invasion . As for the prognostic value of circ‐LARP4, a previous cohort study reports that circ‐LARP4 expression is decreased in tumor tissue than that in paired adjacent tissue, and is negatively correlated with Federation of Gynecology and Obstetrics stages and survival in ovarian cancer patients, which is partially in line with our results .…”

“…In this study, we found that circ‐LARP4 was upregulated in non‐tumor tissue compared with tumor tissue, and tumor tissue circ‐LARP4 high expression was associated with decreased Enneking stage, elevated good response rate, and more satisfactory survival profiles in osteosarcoma patients. Here are several possible explanations for these results: (a) First, like its role in other cancers, circ‐LARP4 might serve as a tumor suppressor in osteosarcoma via inhibiting cancer cell proliferation and invasion or inducing cancer cell senescence via regulating multiple tumor‐related signaling pathways/proteins, for instance, regulating the miR‐424‐5p/LATS1 pathway, resulting in that circ‐LARP4 was downregulated in tumor tissue than non‐tumor tissue, which also led to a negative correlation between tumor circ‐LARP4 high expression and Enneking stage in osteosarcoma patients; (b) second, the further functional experiments in our study showed that circ‐LARP4 enhanced chemosensitivity of osteosarcoma cells to cisplatin and doxorubicin, leading to a better histological response, and may explain the result that tumor tissue circ‐LARP4 high expression associated with elevated good response rate; and (c) third, due to that circ‐LARP4 could serve as a tumor suppressor and enhance chemosensitivity in osteosarcoma cells, a tumor tissue high circ‐LARP4 expression might contribute to a better survival in patients due to less severe disease and better response to chemotherapy …”

A pan-cancer genome-wide analysis reveals tumour dependencies by induction of nonsense-mediated decay

“…Moreover, we found that stomach adenocarcinoma (STAD) tends to have disproportionately higher number of NMD-elicit mutations and a mutator phenotype that selects for NMD-elicit mutations in LARP4B, EIF5B and PTEN . Although the potential relationship between LARP4B or EIF5B and cancer has been previously reported31323334, the link between these genes and hypermutation was previously unrecognized. It is conceivable that NMD-mediated hypofunction of LARP4B or EIF5B permits the hypermutated cancer cells to cope with a high mutation load by delaying translation.…”

The Butterfly Effect of RNA Alterations on Transcriptomic Equilibrium

“…Some members of this superfamily, such as LARP1 [169][170][171][172] and LARP6 [173], control the expression of target transcripts and promote the progression of several cancer types. On the other hand, LARP4A [174] and LARP4B [175] are tumor-suppressive RBPs, which inhibit cancer metastasis and growth, respectively.…”