RNA Molecule, Its Protein May Be Involved in Cancer-related LEMS

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Blood levels of long non-coding RNA LOC338963 and its potential target AP3B2 — a protein in nerve cells — are significantly increased in people with cancer-associated Lambert-Eaton myasthenic syndrome (LEMS) relative to healthy people, LEMS patients without cancer, and people with cancer, a study shows.

The data also suggest that excess AP3B2 levels may affect nerve-nerve and nerve-muscle communication through processes related to molecule transport, breakdown, and recycling.

These findings highlight that LOC338963 and AP3B2 may be specifically involved in LEMS associated with cancer — its most common cause — and may represent new therapeutic targets.

The study, “Plasma lncRNA LOC338963 and mRNA AP3B2 are upregulated in paraneoplastic Lambert-Eaton Myasthenic Syndrome,” was published in Muscle & Nerve.

LEMS is an autoimmune disease wherein the immune system wrongly recognizes a calcium channel protein involved in nerve-muscle communication as foreign, mounting attacks against it and leading to muscle weakness.

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While it can occur spontaneously, LEMS is frequently associated with cancer, most often small cell lung cancer (SCLC), since this calcium channel is also present at the surface of some cancer cells. As such, the antibodies produced by the immune system to fight cancer may also affect neuromuscular communication.

Autoimmune diseases such as LEMS that can be triggered by the body’s immune response against cancer are called paraneoplastic neurological syndromes.

Long non-coding RNAs (lncRNAs), while not resulting in protein production, can regulate the activity of neighboring or distant genes by interacting with DNA, messenger RNA (mRNA), and proteins. Of note, mRNA is the molecule generated from DNA that’s used as a template for protein production.

Increasing evidence suggests that lncRNAs play a key role in immune responses and are involved in the occurrence and development of several autoimmune diseases.

To assess if this is true in LEMS, researchers at the Chinese People’s Liberation Army General Hospital, China, analyzed lncRNA and mRNA blood levels in people with LEMS either associated or not with cancer, and in healthy people.

They first compared lncRNA and mRNA levels between three men with SCLC-associated LEMS who had not received prior treatment and three age-matched healthy men. All were in their 50s.

Results showed the blood levels of 320 lncRNA and 168 mRNA were significantly higher in men with SCLC-associated LEMS than they were in healthy men. The mRNAs that were significantly increased in patients were mainly involved in immune-related processes, analysis showed.

The lncRNA of the LOC338963 gene and the mRNA of the AP3B2 gene — which were located near each other — were found to be both significantly increased by about twofold in men with SCLC-associated LEMS relative to the healthy controls.

This suggested that the higher-than-normal lncRNA LOC338963 levels in these patients may regulate the activity of the neighboring AP3B2 gene and increase the production of its resulting AP3B2 protein.

AP3B2 is part of a protein complex involved in forming specific vesicles that transport molecules within nerve cells at synapses — the site of transmission of chemical messengers and electrical signals between nerve cells, or between nerve and muscle cells.

AP3B2 was previously associated with immune and neurological disorders, further highlighting its potential role in LEMS.

Functional analysis showed that AP3B2 was mainly involved in vesicle transport near the synapse and in processes related to lysosomes, which are cellular compartments where molecular waste — delivered by vesicles — is broken down and/or recycled.

Given that “synapse dysfunction is the main [disease-associated] mechanism of LEMS,” these data “further support the involvement of AP3B2 in the [development] of LEMS by affecting the function of the synapse,” the researchers wrote.

To see if high levels of LOC338963 and AP3B2 mRNA were specific to cancer-associated LEMS, the research team analyzed their levels in nine adults with paraneoplastic LEMS, eight LEMS patients without cancer, and four adults with SCLC.

Among paraneoplastic LEMS patients, four had SCLC, three had liver cancer, one had gastric cancer, and one had a tumor in the thymus, an organ involved in immune responses. Patients with either paraneoplastic LEMS or SCLC had a mean age above 60, while those with LEMS not associated with cancer had a mean age of 48.

Results showed the blood levels of both lncRNA LOC338963 and AP3B2 mRNA were significantly increased in cancer-related LEMS patients relative to those with LEMS but without cancer (by two to five times), and those with SCLC but no LEMS (by five to 15 times).

These findings highlighted that lncRNA LOC338963 and AP3B2 mRNA levels were increased only in those with cancer-related LEMS, suggesting their involvement in the development of this type of LEMS.

Further studies, involving a larger number of patients and with multiple ethnicities, are needed to confirm this potential link and to better understand its underlying molecular mechanisms, the researchers said, adding that if confirmed, LOC338963 and AP3B2 may be promising therapeutic targets for cancer-related LEMS.